Intracellular organelles in health and kidney disease

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NEPHRO-1066; No. of Pages 13 Ne´phrologie & The´rapeutique xxx (2018) xxx–xxx

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Intracellular organelles in health and kidney disease Fateme Shamekhi Amiri Faculty of medicine (poursina), division of nephrology, Imam-Khomeini hospital, National Tehran University of Medical Sciences, Tehran, Iran

A R T I C L E I N F O

A B S T R A C T

Article history: Received 1st November 2017 Accepted 16 April 2018

Subcellular organelles consist of smaller substructures called supramolecular assemblies and these in turn consist of macromolecules. Various subcellular organelles have critical functions that consist of genetic disorders of organelle biogenesis and several metabolic disturbances that occur during nongenetic diseases e.g. infection, intoxication and drug treatments. Mitochondrial damage can cause renal dysfunction as ischemic acute renal injury, chronic kidney disease progression. Moreover, mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury and cardiovascular disease due to oxidative stress in chronic kidney disease. Elevated production of reactive oxygen species could be able to activate NLRP3 inflammasome representing new deregulated biological machinery and a novel therapeutic target in hemodialysis patients. Peroxisomes are actively involved in apoptosis and inflammation, innate immunity, aging and in the pathogenesis of age related diseases, such as diabetes mellitus and cancer. Peroxisomal catalase causes alterations of mitochondrial membrane proteins and stimulates generation of mitochondrial reactive oxygen species. High concentrations of hydrogen peroxide exacerbate organelles and cellular aging. The importance of proper peroxisomal function for the biosynthesis of bile acids has been firmly established. Endoplasmic reticulum stress-induced pathological diseases in kidney cause glomerular injury and tubulointerstitial injury. Furthermore, there is a link between oxidative stress and inflammations in pathological states are associated with endoplasmic reticulum stress. Proteinuria and hyperglycemia in diabetic nephropathy may induce endoplasmic reticulum stress in tubular cells of the kidney. Due to the accumulation in the proximal tubule lysosomes, impaired function of these organelles may be an important mechanism leading to proximal tubular toxicity.  C 2018 Socie ´ te´ francophone de ne´phrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.

Keywords: Endoplasmic reticulum Lysosome Mitochondria Organelles Peroxisome Renal disorders

1. Introduction Subcellular or intracellular organelle, the largest subdivisions of eukaryotic cells, forms the cellular basis of human physiology. A complete set of organelles such as nucleus, mitochondria, endoplasmic reticulum, peroxisoms and lysosomes are always inherited maternally and proliferation, also termed organelle biogenesis, of these endowed organelles leads to an increased number and size of specialized membrane-bound cell compartments [1]. In addition to organelle-to-organelle communication within the cell, autocrine, paracrine and even endocrine mechanisms can be conveyed through cell-derived vesicles such as microparticles and exosomes. These organelles carry mitochondrial ribonucleic acid (miRNAs), hormonal factors and cell surface E-mail address: [email protected]

receptors, which transmit information/signal transduction from originally to receiving cells [2]. Organellar function in health and kidney disease has been described in Tables 1 and 2.

2. Methods This paper has written based on searching PubMed and Google Scholar to identify potentially relevant articles or abstracts. The mentioned search included the following search terms: organelles, organelles in kidney cells, and intracellular organelles in kidney cells. Search terms were used both discretely and combined with each other using the boolean operator and. The author reviewed the bibliographies of all selected articles to identify additional relevant studies. Continuation of discussion about intracellular organelles are as follows.

https://doi.org/10.1016/j.nephro.2018.04.002 C 2018 Socie ´ te´ francophone de ne´phrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved. 1769-7255/

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2 Table 1 Organellar functions in health in kidney cells. Organelle

Functions

Mitochondria

Mitochondrial fusion and fission for mitochondrial morphology maintenance, mtDNA integrity, regulating cellular survival and death, transmitting redox-sensitive signals, participating in metabolic processes Biosynthesis for steroids, cholesterol and other lipids Subcellular entrance for a number of secretory and structural proteins and providing a unique environment for appropriate protein folding and assembly to produce functional, mature proteins Active participation in apoptosis, innate immunity, inflammation Biosynthesis of signaling molecules, polyunsaturated fatty acids, bile acids, plasmalogens and purines Beta-oxidation of fatty acids and hydrogen peroxide, catalase turnover, degradation of prostaglandins, VLCFA, aminoacids Peroxisomal autophagy regulates and maintains homeostasis by eliminating aged, damaged and dysfunctional cellular constituents Disposal and recycling of worn out and damaged cellular macromolecules and organelles as well as the digestion of the cargo is brought about by hydrolases residing in the lysosomal lumen, and the products are recycled back to the cytosol via diffusion and specific transport channels or released to the extracellular space by exocytosis

Endoplasmic reticulum

Peroxisome

Lysosome

mtDNA: mitochondrial deoxy ribonucleic acids; VLCFA: very long chain fatty acids.

Table 2 Organellar dysfunctions in kidney diseases. Organelle

Dysfunction

Mitochondria

A. Glomerular Podocyte Foot process effacement Detachment Apoptosis B. Tubular epithelial cells Apoptosis/necrosis Epithelial-mesenchymal transition C. Endothelial cells Apoptosis/necrosis Endothelial-mesenchymal transition A. Glomerular disease Congenital nephrotic syndrome Membranous nephropathy Ischemic injury B. Tubular disease Ischemic injury NSAID Antibiotics Anti-cancer agents Immunosupressant injury Heavy metal intoxication C. Impairment of transcriptional activity of erythropoietin by endoplasmic reticulum stress D. ER stress-induced apoptosis pathway contributed to the insult of tubular cells by proteinuria. ER stress may subsequently lead to tubular damage by activation of caspase-12 E. A crucial role for the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury A. Proximal tubules Ischemic AKI B. Septic AKI C. Diabetic nephropathy D. Renal cancer PPAR-a E. FFA-induced peroxisomal dysfunction exacerbates DN and endogenous catalase plays an important role in protecting the kidney from diabetic stress through maintaining peroxisomal and mitochondrial fitness A. Depressed activities of cathepsins due to elevated lysosomal pH, a shift of lysosomal pH above the optimum of the acidic cathepsins seem to be a key factor in their impaired activities in mesangial cells B. Gentamicin may reduce renal protein catabolism by decreasing the activity of the key proteolytic enzymes, cathepsins B and L are proteolytic activators of other lysosomal enzymes, their reduced activity may also decrease the activities of other lysosomal enzymes C. Role of kidney lysosomes in the accumulation and catabolism of exogenous proteins D. Myostatin mediated CKD-induced muscle catabolism via coordinate activation of the autophagy and the ubiquitin-proteasome systems E. Transformation and cancer progression are characterized by dramatic changes in lysosomal volume, composition and cellular distribution

Endoplasmic reticulum

Peroxisome

Lysosome

AKI: acute kidney injury; CKD: chronic kidney disease; DN: diabetic nephropathy; ER: endoplasmic reticulum; FFAs: free fatty acids; mtDNA: mitochondrial deoxy ribonucleic acids; NSAID: non-steroidal anti-inflammatory; PPARs: peroxisome proliferator activated receptors.

3. Organelle and kidney 3.1. Mitochondria and kidney The mitochondrion is a double membrane organelle that exists in most eukaryotic cells except from mature erythrocytes. The double-membrane structure forms three separate regions and two compartments, termed the outer mitochondrial membrane

(OMM), intermembrane space, cristae formed by inner mitochondrial membrane (IMM), and matrix. The OMM has pores that allow passive diffusion of molecules smaller than 5000 Daltons. Larger molecules pass through the mitochondrion via translocases on the OMM. When irreparable damage to cells occurs, the permeability of the OMM increases and proteins located in the intermembrane space such as cytochrome C, flow out and initiate the apoptosis program. Owing to the numerous folds of cristae with oxysomes,

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the area of the IMM is about five times greater than that of the OMM. The IMM is embedded with abundant proteins that perform redox reactions, synthesize adenosine triphosphate (ATP), block ionic diffusion, and regulate mitochondrial dynamics. The IMM also encloses the matrix, where the oxidative phosphorylation (OXPHOS) enzyme and mitochondrial genetic material reside. Mitochondrial respiratory chain is composed of five enzyme complexes (I–V) that are embedded within the IMM. These complexes contain complex I (NADH-ubiquinone oxyreductase), complex II (succinate-ubiquinone oxyreductase), complex III (ubiquinol-ferricytochrome C oxidoreductase), complex IV (cytochrome C oxidase), and complex V (ATP synthase). Within the mitochondrial respiratory chain, ubiquinone, or coenzyme Q10 (CoQ10), plays a crucial role in shuttling electrons from complexes I and II to complex III and then are transferred to complex IV by cytochrome C, which accumulates sufficient energy to motivate complexes I, III, and IV to pump the protons from the matrix to intermembrane space. Due to generated electrochemical gradient, the protons influx back to the matrix through complex V to form ATP from ADP and inorganic phosphate (Fig. 1). Mitochondria are energy-producing organelles that also conduct other key cellular tasks, including the regulation of cytosolic calcium levels and tissue oxygen gradients, hydrogen peroxide (H2O2) signaling and the modulation of apoptosis. Importantly mitochondria have emerged as organelles that receive, integrate and transmit signals, thus playing a critical role in cellular responses to a variety of stimuli. Hence, it is apparent that mitochondrial damage may lead to the impairment of various aspects of tissue functioning

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[3]. Mitochondria undergo function-defining dynamic shape changes, communicate with each other, regulate gene expression within the nucleus, modulate synaptic transmission within the brain, release molecules that contribute to oncogenic transformation and trigger inflammatory responses systemically, and influence the regulation of complex physiological systems [4]. Mitochondria have their own small genome of circular mitochondrial double-stranded deoxyribonucleic acid (mtDNA), which is considered a remnant of their endosymbiotic origin from an ancestral a-proteobacterium that incorporated into eukaryotic cells early in evolution [5]. Work in skeletal muscle and other tissues shows that mitochondrial biogenesis and its attendant processes enhance metabolic pathways such as fatty acid oxidation and decreased mitochondrial reactive oxygen species (ROS) production to ameliorate injury from tissue hypoxia, glucose, fatty acid overload and aging. Benefits from maneuvers that promote pathways such as increases of extramitochondrial antioxidants, heme oxygenase 1, Bnip 3 and cytochrome 2 that are elicited by the same coactivators and transcription factors. MtDNA is apt to be exposed to reactive oxygen species stress without histone protection. Moreover, almost the entire coding regions lack repair mechanisms. As a result, it is highly susceptible to damage and mutations with a 10 to 1000-fold greater mutation rate than DNA. The main external risk factors of mtDNA damage include ROS, ultraviolet (UV) light, ionizing radiation, allergical agents, base analouges, modified-induced base pair variations and aging. Even with no external damage, mtDNA undergoes natural damage such as base mismatches during replication, spontaneous base changes,

Fig. 1. Schematic presentation of mitochondrial components and respiratory chain function in organelle. Pyruvate passes through mitochondrial membranes and is converted to acetyl-coenzyme A by pyruvate dehydrogenase complex. Then acetyl-coenzyme A enters tricarboxylic acid and produces nicotine adenine dinucleotide, flavin adenine dinucleotide with hydrogen ions. NADH, FADH and hydrogen ions provide electrons and protons for respiratory chain. Acetyl-coA: acetyl-coenzyme A; ADP: adenosine diphosphate; ATP: adenosine triphosphate; FAD: flavin adenine dehydrogenase; IMM: inner mitochondrial membrane; IMS: intermitochondrial membrane space; NAD: nicotine adenine dehydrogenase; OMM: outer mitochondrial membrane; PDC: pyruvate dehydrogenase complex; Pi: inorganic phosphate.

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single stranded breakage, double-stranded breakage and interstranded crosslinking. Additionally, mtDNA is equipped with inadequate and inefficient repair mechanisms. Consequently, mtDNA mutations cause mitochondrial dysfunction, including reduced ATP synthesis, elevated intracellular calcium levels (resulting from calcium pump inactivation), activated phospholipases, and decomposition of membrane phospholipids. As such previously said, mitochondria are responsible for more than 90% of energy production by OXPHOS in the human body. The coordination between the tricarboxylic acid (TCA) cycle and the electron transport chain is the main process for ATP production. Mitochondrial homeostasis is closely regulated by mitochondrial biogenesis, including the control of mtDNA replication, mitochondrial dynamics such as mitochondrial fragmentation and mitophagy (autophagic clearance of damaged mitochondria). This machinery acts to maintain mitochondrial structure and function. Its derangement induces mitochondrial damage that is often associated with the induction of mitochondrial ROS production, apoptosis and mitochondrial permeability transition (MPT) pore opening. These changes in turn lead to the development and progression of diseases related to mitochondrial dysfunction. Mitochondrial turnover is an integral aspect of the maintenance of mitochondrial quality. In this process, dysfunctional mitochondria are selectively eliminated and replaced through an increase in the number of pre-existing mitochondria (biogenesis). Mitochondrial diseases are classified into inherited mitochondrial cytopathies and acquired mitochondrial dysfunction in kidney disease. Defects in the mitochondrial respiratory chain underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. Genetic or small molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Several studies confirm that chronic hypoxia exposure to breathing 11% O2 activates the endogenous hypoxic response. Hypoxia does not correct the proximal lesion within mitochondrial complex I, but rather prevents the onset of subsequent biochemical and histopathological defects. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease [6]. The kidney is a highly energetic organ and rich in mitochondria. Mitochondria in the kidney are valuable to insults like hypoxia in ischemic acute renal injury or toxins filtered from blood. The kidney consumes a large amount of energy supplied as ATP from mitochondria, which drive directly, the reabsorption of large quantities of fluid and solutes across the renal tubular epithelium. Any disruption in this supply is likely to cause renal dysfunction. However a reduced supply of ATP may not be the only mechanism by which the mitochondria can affect the renal function [7]. Mitochondrial sirtuin 3 (SIRT3) which belongs to an evolutionary conserved family of nicotinamide adenine dinucleotide (NAD + ) – dependent deacetylases is a key regulator of the mitochondrial respiratory chain, ATP production, and fatty acid b-oxidation and it exerts an antioxidant activity. Changes in SIRT3 expression are critical in the pathophysiology of several diseases such as metabolic syndrome, diabetes, cancer and aging. In experimental acute kidney injury, impairment of renal function and development of tubular injury are associated with SIRT3 reduction and mitochondrial dysfunction in proximal tubuli [8]. Studies have shown significantly increased ROS production [9], higher mitochondrial-encoded subunit I of cytochrome C oxidase (COX-I) and nuclear-encoded subunit IV (COX-IV) protein levels of complex IV in chronic kidney disease (CKD) IV–V and hemodialysis (HD) patients and reduction of mean enzymatic activity of complex IV in peripheral blood mononuclear cells of

patients with stage IV–V of CKD (64%) and HD (46%) patients, thereby demonstrating the close association between mitochondrial dysfunction and chronic kidney disease progression [10]. Moreover, mitochondrial dysfunction is an early event in aldosterone-induced podocyte injury [11]. The mitochondriainduced Nod-like or Nucleotide-binding domain leucin-rich repeat-containing receptors (NLR) pyrin domain-containing protein 3 (NLRP3) inflammasome activation has been also reported by other groups in animal model of proteinuria-induced renal tubular injury [12]. Damaged mitochondria of uremic patients through an elevated production of ROS could be able to activate NLRP3 inflammasome representing new deregulated biological machinery and a novel therapeutic target in HD patients (Fig. 2). Granata et al. in an original study assessed mRNA levels of NLRP3 inflammasome, caspase-1 (CASP-1), apoptosis-associated specklike protein containing a caspase recruitment domain (ASC), IL-1b, IL-18 and P2X7 receptor using real time-polymerase chain reaction (RT-PCR), western blot, FACS analysis, confocal microscopy and microarray in 15 hemodialyzed patients. Active forms of CASP-1, IL-1b and IL-18 significantly up-regulated in HD patients and elevated mitochondrial ROS level, colocalization of NLRP3/ASC/ mitochondria in peripheral blood mononuclear cells from HD patients and down-regulation of CASP-1, IL-1b and IL-18 protein levels in immune cells of HD patients were resulted. All together these data showed that NLRP3 inflammasome was activated in uremic patients undergoing dialysis treatment [13]. Mitochondrial dysfunction is a key issue for the progression of tubular damage in acute kidney injury (AKI). Importantly the mitochondrial dysfunction significantly affects the other organelle dysfunction such as endoplasmic reticulum and it will be master player of complex organelle network in acute kidney injury. Mitochondrial dysfunction is thought to be a leading factor in the pathogenesis of septic acute kidney injury, the most common cause of acute kidney injury. Peroxisome proliferator-activated receptor gamma (PPARg) coactivation-1 alpha (PGC-1a) is a master regulator of mitochondrial biogenesis and it may play an important role in recovery from septic acute kidney injury via the maintenance of tubular mitochondrial biogenesis. Dynaminrelated protein 1 (Drp1) a mitochondrial fission mediator is rapidly activated following acute kidney injury, such as in ischemia reperfusion and cisplatin-induced nephropathy, and induces mitochondrial fragmentation and subsequent renal tubular cell apoptosis. These findings indicate that either or both increased dynamin-related protein-1 (Drp1) and decreased mitofusin 2 (Mfn2) exacerbate tubular damage via an imbalance in mitochondrial fission and fusion with subsequent enhancement of mitochondrial fragmentation, and might thereby contribute to kidney disease including acute kidney injury [14]. Mitochondria play a crucial role in the regulation of the endogenous pathways of apoptosis activated by oxidant stress. Nuclear factor-kappa B (NFkB) is a central integration site for pro-inflammatory signals and oxidative stress. Raj et al. in an original study separated peripheral blood mononuclear cells (PBMC) from end stage renal disease (ESRD) patients before HD and during the last 10 min of HD. Intracellular generation of ROS, mitochondrial redox potential and PBMC apoptosis were determined by flow cytometry. Plasma levels of IL-6, IL-6 soluble receptor and IL-6gp130 were higher end-HD compared to pre-HD. IL-6 secretion by the isolated PBMC increased end-HD. Percentage of lymphocytes exhibiting collapse of mitochondrial membrane potential, apoptosis and generation of superoxide and hydrogen peroxide were higher at end-HD than pre-HD. NF-kB activation, expression of B-cell lymphoma protein2 and heat shock protein-70 increased during HD. In conclusion, intradialytic activation of cytokines, together with impaired mitochondrial function promotes generation of ROS culminating in augmented PBMC apoptosis. There is concomitant activation of

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Fig. 2. Mitochondrial dysfunction, sensed by the exposure of mitochondrial deoxyribonucleic acids (mtDNAs), mitochondrial damaged associated molecular patterns (DAMPs) and pathogen-associated molecular proteins (PAMPs) to the cytosol, alterations in metabolic levels, and/or increased mtROS, activates the NLRP3 inflammasome. The dysfunction can result from the activation of pathways that sense the presence of microbes or from the direct targeting of mitochondria by pathogens. It can also result from non-infectious diseases such as diabetes, gout, and atherosclerosis. This schematic presentation depicts close association between inflammation and mitochondrial dysregulation in chronic kidney disease-hemodialysis patients. AD: Alzheimer’s disease; AKI: acute kidney injury; AS: atherosclerosis; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; CKD: chronic kidney disease; LPS: lipopolysaccharide; MS: metabolic syndrome; NF-kB: nuclear factor-kappa B; NLRP3: nucleotide binding domain-leucin rich repeat pyrin domain-containing 3; mtROS: mitochondrial reactive oxygen species; OS: osteoarthritis; TNF: tumor necrosis factor; T2DM: type 2 diabetes mellitus; TLR: toll-like receptor.

pathways aimed at attenuation of cells stress and apoptosis during HD [15]. Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD. In study by Gamboa et al. tested the hypothesis that mitochondrial volume density (i.e. mitochondrial number) decreases in skeletal muscle from patients with CKD and mitochondrial function decreases with the severity of CKD. Moreover, they measured mtDNA copy number from PBMC, lactate concentrations, and the ratio of plasma isofurans to F2-isoprostanes in patients of different stages of CKD. Skeletal muscle biopsies for analysis of mitochondrial ultrastructure by electron microscopy were obtained from 11 patients with CKD stage 5 on maintenance hemodialysis (MHD) and 17 controls. They found that mitochondrial volume density and mitochondrial DNA copy number were decreased, whereas B-Cell Leukemia/Lymphoma-2 (BCL-2)/Adenovirus interacting protein 3 (BNIP3), a marker of mitophagy was

increased in skeletal muscle in patients with CKD stage 5. Furthermore, they found that mtDNA copy number in PBMCs is decreased in patients on MHD compared to controls with no CKD. Lactate levels are higher in patients with CKD stage 5 on MHD, a population with high mortality rates and an increased incidence of heart failure. Levels of isofurans were higher in patients with CKD stage 5 on MHD than in patients with CKD stages 1–4. Increased ratio of isofurans to F-2 isoprostanes suggests a preferential production of isofurans in patients undergoing MHD. These findings may be a consequence of mitochondrial dysfunction. MtDNA copy number may be a more sensitive marker of mitochondrial function since it is already decreased by CKD stage 3–4. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD [16]. Another study by Balakrishnan et al. examined the effect

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of resistance exercise training on skeletal muscle mtDNA copy number and determined its association with skeletal muscle phenotype (muscle mass and strength). They suggested that the mitochondrial dysfunction observed with chronic disease could potentially be restored with the exercise modality [17]. Yuan et al. reported that the activation of the SIRT1-PCG-1a axis in mitochondria ameliorates aldosterone-induced podocyte injury in the cultured podocytes. They further showed that overexpression of SIRT1 or PGC-1a inhibited the aldosterone-induced mitochondrial dysfunction and podocyte injury [18,19]. Hyper-IgG4associated abnormalities are common denominators for several autoimmune fibroinflammatory diseases that can affect any organ from the salivary glands to the pancreas or kidneys. Characteristic pathological features in various affected sites consist of lymphoplasmacytic infiltration with IgG-4 positive plasma cells, sortiform fibrosis, and variably elevated levels of IgG4. Kidney lesions are usually accompanied by tubulointerstitial nephritis. Glomerular lesions, including membranous nephropathy, have been reported less frequently. Buelli et al., in a case report, demonstrated patient’s IgG4 cause a drop in cell pH followed by mitochondrial dysfunction, excessive ROS production and cytoskeletal reorganization in cultured podocytes. The onset of membranous nephropathy in a subset of patients could be due to IgG4 antibodies recognizing with IgG4 related disease [20]. 3.2. Peroxisome and kidney In 1954, Swedish doctoral student Johannes Rhodin described for the first time small spherical organelles and then named microbodies. These organelles were later biochemically characterized by De Dune and because of the high content of H2O2metabolizing enzymes, the structural term, microbodies, was replaced by a more functional term, peroxisomes in 1965. Mammalian peroxisomes are 0.1–0.5 mm-sized single membrane organelles present in the majority of eukaryotic cells with the highest abundance in the liver and the kidney. Peroxisomes possess specific proteins called peroxins that are encoded by corresponding PEX genes [21,22]. Peroxisomes membrane proteins are recognized and bound by cytosolic protein 19 (PEX19) via a specific mitochondrial peroxisomal targeting signal (mPTS). PEX19 interacts with peroxisome membrane-anchored PEX-3, which is followed by release and incorporation of the transported proteins into the membrane. Then, PEX19 is exported back to the cytoplasm [23,24]. Endoplasmic reticulum (ER) was postulated to provide the initial seed for recruiting Pex3p and Pex16p required for peroxisome assembly. The numerous metabolic tasks require reliable substrate and cofactor transport systems, in particular for the two most important peroxisomal tasks, the b-oxidation of fatty acids (FAO) and H2O2 metabolism. Most fatty acids are metabolized by b-oxidation, which involves the removal of two carbons at the carboxyl terminus of the molecule and is carried out in peroxisomes and mitochondria. Renal cortex and particularly proximal tubules are heavily dependent on FAO as the major source of energy for numerous transport systems localized in this part of the nephron. FAO is exclusive to peroxisomes in prokaryotic organisms. In eukaryotes and particularly in mammals, peroxisomes cooperate closely with mitochondria and form a strategic partnership in cell energy metabolism. Mitochondria preferentially oxidize short and medium-chain fatty acids, whereas peroxisomes metabolize very long-chain fatty acids (VLCFA) with more than 22 carbons. Peroxisomal enzymes shorten the long chain of VLCFA, which are subsequently transported to mitochondria and oxidized to acetyl-CoA. Since peroxisomes do not contain respiratory chain enzymes, peroxisomal FAO is not directly coupled to generation of ATP (indirectly through anaplerotic reactions for mitochondria) and most of the energy is released as

heat. Peroxisomal FAO is unique due to the generation of H2O2, a by-product of the oxidative reactions. The results of numerous studies indicated that inhibited or dysfunctional FAO exhibits negative effects on renal injury. Functional FAO prevents accumulation of fatty acids, their peroxidation, and formation of lipid aldehydes that can further aggravate renal injury. Treatment with PPARa agonists such as fibrates preserves FAO and shows nephroprotective effects in AKI. The peroxisomal membrane is permeable to small metabolites upto 500 Da in size. The internalization of large molecules such as fatty acids, adenosine triphosphate or coenzyme A, requires specific receptors. Several membrane-incorporated ATP-binding cassette (ABC) transporters facilitate the import of fatty acids processed by peroxisomal oxidation of fatty acids. Three ABC transporters belonging to subfamily D have been identified in mammalian peroxisomes. ABCD3 also known as peroxisomal membrane protein 70 (PMP70) is experimentally used as a structural marker of peroxisome. Peroxisomes are actively involved in apoptosis and inflammation, innate immunity, aging and in the pathogenesis of age related diseases, such as diabetes mellitus and cancer. PPAR represents a family of nuclear receptors composed of three members: PPARa, PPARb/d and PPARg. PPARa is highly expressed in cells with high fatty acid oxidation activity such as: brown adipose tissue, liver, kidney, heart and skeletal muscle. PPARb in the highest expression is found in the gut, kidney and heart. PPARg is mainly expressed in adipose tissue, and to a lesser extent in colon and immune system [25]. PPARa is stimulated by hypolipidemic drugs (fibrates) and by naturally occurring ligands of the arachidonic cascade, such as leukotrienes. Upon activation, PPARa translocates into the nucleus and binds to a specific DNA sequence called PPAR response element located in the promoter region of genes encoding peroxisomal (and mitochondrial) FAO enzymes. Several PPARa independent activators of peroxisomes such as PGC-1a or SIRT1 have been reported. About 50 peroxisomal enzymes have so far been identified which contribute to several crucial metabolic processes such as b-oxidation of fatty acids, biosynthesis of ether phospholipids and metabolism of reactive oxygen species and render peroxisomes indispensable for human health and development. It became obvious that peroxisomes are highly dynamic organelles that rapidly assemble, multiply and degrade in response to metabolic needs. Peroxisomes have well-established roles in protection of the nervous system and in detoxification in the liver and kidney [26–28]. Peroxisomes are highly metabolic, autonomously replicating organelles that generate ROS as a by-product of fatty acid b-oxidation. Consequently, cells must maintain peroxisome homoeostasis, or risk pathologies associated with too few peroxisomes such as peroxisome biogenesis disorders, or too many peroxisomes, including oxidative damage and promoting diseases such as cancer. In response to reactive oxygen species, ataxiatelangiectasia mutated (ATM) signaling activates protein unc-51 like kinase (ULK1) and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 mono-ubiquitination at K209 and recognition of ubiquitinated PEX5 by the autophagy adapter protein P62, directing the autophagosome to peroxisoms to induce pexophagy. These data reveal an important new role for ATM in metabolism as a sensor of ROS that regulates pexophagy [29]. Peroxisome oxidases generate excessive amount of H2O2 and require reliable scavenger mechanisms. Dysfunction of peroxisome antioxidant enzymes may result in H2O2 leakage into the cytoplasm with harmful consequences for the cell. There is increasing evident on the close connection between peroxisomes, mitochondrial, cellular redox homeostasis. The interaction of peroxisomal catalase causes alterations of mitochondrial membrane proteins and stimulates generation of mtROS. It is important to mention the low (hermetic)

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concentrations of ROS function as mediators of cell signaling. Low hermetic levels of H2O2 stimulate anti-aging pathways (e.g. activation of autophagy responsible for all surveillance and removal of aged organelles). High concentrations of H2O2 exacerbate organelles and cellular aging. Cells regulate the number of organelles through continual interplay between biogenesis, degradation. Experimental studies demonstrated that peroxisomes have a half-life of circa 48 hours under basal conditions and peroxisomes are primarily degraded by autophagy. Autophagy is a highly conserved lysosomal dependent pathway that maintains the quality of cellular components through continual removal of redundant or damaged proteins or entire organelles. The molecular basis of autophagy-mediated degradation of peroxisomes called pexophagy (lysosomal autophagy of peroxisome). The most important pathway for removal of peroxisomes is autophagy. Three main types of autophagy have been described: Macroautophagy, microautophagy and chaperone-mediated autophagy. The dominant form of organellar autophagy in mammalian cells is macroautophagy. The autophagosome with engulfed proteins or organelles, moves through the cytoplasm and fuses with the lysosome. The selective autophagy of peroxisomes requires the presence of specific cargo receptors. Among them, P62/SQSTM1 has been associated with mammalian pexophagy. Since P62/ SQSTM1 is designated by autophagy at the same time as its ubiquitinated cargo, this protein has been used as a marker of the autophagy/pexophagy flux. In other words, the inhibition of autophagy leads to accumulation of P62/SQSTM1 and vice versa. Pexophagy is the main degradation mechanism maintaining peroxisome homeostasis in mammalian cells. It was recently shown that downregulation of PEX14 partly protects peroxisomes from NBR1-induced pexophagy. Although the authors postulated impairment of PEX5 recruitment to the peroxisomes via PEX14 as a cause, their results do not unequivocally prove PEX5 recognition by NBR1, since PEX14 directly interacts with LC3-II under nutrient starvation conditions [30]. Peroxisome is most abundant in the liver and the kidney. In kidney, peroxisomes couple the oxidation of L- and D-aminoacids to the oxidation of harmful molecules filtered from the blood, such as lipid-based xenobiotics [31]. They are particularly dense in proximal tubules with negligible presence of glomeruli, distal tubules, and collecting ducts. During tubular regeneration after acute kidney injury (AKI), mitochondria and endoplasmic reticulum appear before peroxisomes. Peroxisomes regenerate later at the same time as lysosomes. In mercuric chloride-induced acute tubular necrosis, peroxisomes appear on the fourth day of regeneration and their number reaches the normal distribution in the fourth week. Proximal tubular cells are the major targets of ischemic injury during acute renal failure. Increased parenchymal levels of free fatty acids and decreased ATP levels are consistent findings in the ischemic kidney. Mitochondria have long been considered to play a central role in cell dysfunction during ischemia-reperfusion and hypoxia-reoxygenation kidney injury. ROS are the main etiological agents in the pathophysiology of ischemia-reperfusion injury. Reperfusion of ischemic kidney leads to excessive generation of ROS and further aggravates the ischemic injury. Peroxisomal antioxidant mechanisms, including superoxide dismutase, glutathione peroxidase and the key enzyme catalase, participate in the detoxification of peroxisomal (and cellular) ROS. Renal ischemia decreases FAO and catalase activity. The reperfusion phase following ischemia generates significant oxidative stress. The accumulation of unmetabolized fatty acids augmented by inactivated and/or degraded catalase promotes lipid peroxidation and cellular damage. Interestingly, renal ischemiareperfusion injury exhibits negative effect also on distant organs. Fifty minutes of renal ischemia and subsequent reperfusion induce oxidative cardiac injury characterized by myocardial levels of lipid peroxides and decreased activities of myocardial antioxidant

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enzymes. Sepsis is the most common cause of AKI in critically ill patients. Magnetic resonance imaging shows alterations in renal paranchyma already 6 hours, after septic insult and underline the importance of early subclinical alterations in septic AKI. The S2, S3 segment of proximal tubuli have the highest density of peroxisomes, the S1 segment lacks these organelles. Both, S2 and S3 segments exhibit severe oxidative peroxisome damage already 4 hours after administration of endotoxin, even before the mitochondrial injury occurs. Dysfunctional pexophagy impairs regeneration of peroxisome and induces intraorganellar redox imbalance. Different from the sublethal model of endotoxic AKI, the decline of autophagy in severe polymicrobial sepsis appears to aggravate tubular injury. The initially upregulated and later downregulated autophagy/pexophagy (coordinated biphasic response) seem to be protective to endotoxic AKI. Hence, accurately dosed and precisely coordinated activation and deactivation of autophagy/pexophagy play a critical role in organellar and cellular homeostasis during septic renal injury. Peroxisomal alteration reported in various models of AKI may represent mechanisms involved in more common kidney disorders. However, at a lower intensity and with long-term implications, experimental data indicate an important role for ROS in the nephropathy of diabetes. The most of the peroxisome studies in diabetic nephropathy focused on the oxidative stress and the role of peroxisomal catalase. Farnesyl transferase catalyzes farnesylation of small GTPase proteins such as Ras and Rho and plays an important signaling role in the regulation of cell proliferation. Because of defective mitochondrial oxidation in renal cancer cells obtain their energy primarily from glycolysis rather than oxidative phosphorylation and renal cancer cells have not peroxisomes [32]. Pex11a deficiency impairs peroxisome elongation and abundance and peroxisomal fatty acid b-oxidation, subsequently contributing to increased lipid accumulation in the liver (steatosis) or kidney (chronic kidney disease). Elevation of butyrate availability (directly through administration of butyrate producing probiotics plus fiber) induces PPARa and Pex11a and the genes involved in peroxisomal fatty acid b-oxidation increases peroxisome abundance and improves lipid metabolism [33]. Weng et al., in an experimental study, investigated role of Pex11deficiency-induced derangements of the systems in proximal tubule cells and the aggravation of tubulointerstitial lesions in chronic kidney disease. Histological analyses showed that the numbers of functional peroxisomes in proximal tubule cells was reduced in Pex11a knockout mice. Deoxycorticosterone acetatesalt-treated Pex11a knockout mice exhibited greater interstitial lesions than deoxycorticosterone acetate-salt-treated Pex11a wild type mice in terms of tubular lipid accumulation, blood pressure, urinary albumin, urinary N-acetyl-b-D-glucoseaminidase, urinary 8-iso-prostane, and the histological evaluation of fibrosis and inflammation. These results show that proximal tubule peroxisome play an important role in proteinuria-induced interstitial lesions. The activation of tubular peroxisomes might be an excellent therapeutic strategy against chronic kidney disease [34]. Negishi et al., in an experimental animal study, investigated the role of liver fatty acid binding protein (L-FABP) in acute kidney injury caused by cisplatin (CP) in normal mice and in mice transgenically overexpressing human L-FABP. There was increased peroxisomal labeling in the proximal tubules of control and CPtreated mice when either treated with fibrate, a known PPARa ligand. L-FABP expression, not detected in control or CP-treated mice, was significantly increased in the proximal tubules of fibratetreated mice of either group. In the transgenic mice, CP increased the shedding of h-L-FABP in the urine, which was decreased by fibrate, as was the acute renal failure. This study showed that fibrate may improve CP-induced acute renal failure due to both peroxisome proliferation and increased L-FABP in the cytosol of the

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proximal tubule [35]. Li et al., in an experimental animal study, investigated the effects of increased expression of proximal tubule PPARa in a mouse model of renal fibrosis. After 5 days of unilateral ureteral obstruction PPARa expression was significantly reduced in kidney tissue of wild-type mice but this downregulation was attenuated in proximal tubules of PPARa transgenic (Tg) mice. When compared with wild-type mice subjected to unilateral ureteral obstruction (UUO), PPARa Tg mice had reduced mRNA and protein expression of proximal tubule transforming growth factor (TGF)-b1, with reduced production of extracellular matrix proteins including collagen 1, fibronectin, a-smooth muscle actin, and reduced tubulointerstitial fibrosis. UUO-mediated increased expression of microRNA 21 in kidney tissue was also reduced in PPARa Tg mice. Overexpression of PPARa in cultured proximal tubular cells by adenoviral transduction reduced aristolochic acidmediated increased production of TGF-a; demonstrating PPARa signaling reduces epithelial TGF-a production. Flow cytometry studies of dissociated whole kidneys demonstrated reduced macrophage infiltration to kidney tissue in PPARa, Tg mice after UUO. Increased expression of proinflammatory cytokines including interleukin-1b (IL-1b), IL-6, and tumor necrosis factor-a (TNFa) in wild-type mice was also significantly reduced in kidney tissue of PPARa Tg mice. In contrast, the expression of antiinflammatory cytokines IL-10 and arginase-1 was significantly increased in kidney tissue of PPARa Tg mice when compared with wild-type mice subjected to UUO. This study demonstrates that several mechanisms by which preserve expression of proximal tubule PPARa reduces tubulointerstitial fibrosis and inflammation associated with obstructive uropathy [36]. Peroxisome homeostasis disruption may be the basis of several human diseases and could be related to organism physiology. This link to diseases is also true for pexophagy. For example an endotoxin-induced stress study revealed that pexophagy prevents the accumulation of functionally compromised peroxisomes, altered redox balance and renal damage in human and mice vascular endothelial cells exposed to liposaccharides [37]. Feldkamp et al., in an experimental study, investigated the effects of nonesterified fatty acids (NEFA) in causing the sustained energetic deficit in kidney proximal tubules after hypoxia-reoxygenation. They concluded that NEFA overload is the primary cause of energetic failure of reoxygenated proximal tubules and lowering NEFA substantially contributes to the benefit from supplementation with alphaketoglutarate plus malate (a-KG/MAL) [38]. PO-ER associations have been suggested to impact on diverse number physiological processes including lipid metabolism, phospholipid exchange, metabolite transport, signaling and PO biogenesis. It has been identified that PO membrane protein acyl-coenzyme A-binding domain protein 5 (ACDB5) as a binding partner for the resident ER protein vesicle-associated membrane protein-associated protein B (VAPB). It has been shown that ACDB5-VAPB interaction regulates PO-ER associations. Furthermore, it has been demonstrated that loss of PO-ER association perturbs PO membrane expansion and increases PO movement [39]. Peroxisomes and the endoplasmic reticulum cooperate in cellular lipid metabolism and form tight structural associations, which were first observed in ultrastructural studies decades ago. Peroxisomes have long been viewed as semiautonomous, static and homogenous organelles that exist outside the secretory and endocytic pathways of vesicular flow. Moreover, evidence supports the view that peroxisomes actually constitute a dynamic endomembrane system that originates from the endoplasmic reticulum [40]. Schlu¨ter et al. in an experimental study retrieved 103 peroxisomal proteins as components of the peroxisomal proteome and additional fungi and mouse proteins without human orthologue. Results of this study indicate that the other two markers, the components of the import machinery Pex10 and Pex12, also exhibit a relationship to ER, although of

different nature. These proteins are E3 ubiquitin ligases and belong to a subclass that harbors a Zn-RING finger domain, able to bind to E2 ubiquitin-conjugating enzymes. This Zn-RING domain is widely represented in ER eukarya, absent in prokarya although strikingly, and also present in a few viruses. Interestingly, two membranebound ER resident proteins are E3s ubiquitin ligases with a Zn-RING domain that participate in the ER-associated degradation (ERAD) process for turnover of misfolded and short-lived proteins. The ERAD process is based on retrograde protein translocation from the ER membrane to the cytosol, mediated by targeting through a tetratricopeptide (TPR)-containing protein (Hrd3), association with ubiquitin-conjugating enzymes (E2s) which are linked to the membrane by the E3 ubiquitin ligases, subsequent ubiquitination, and finally recruiting of the 26S proteasome to the ER membrane by the adenosine triphosphatase (ATPase) Cdc48 complex, for substrate degradation [41]. 3.3. Endoplasmic reticulum and kidney ER is a type of organelle in the cells of eukaryotic organisms that forms an interconnected network of flattened membrane-enclosed sacs or tubes. The functions of the ER can be summarized as the synthesis and export of proteins and membrane lipids. The ER seems to be having many general functions including the folding of protein molecules in sacs called cisternae and the transport of synthesized proteins in vesicles to the Golgi apparatus (Golgi complex and trans-Golgi network). From the trans-Golgi network, proteins can be sorted to several sites including lysosomes and to the plasma membranes for insertion or release into the extracellular space [42]. Correct folding of newly made proteins is made possible by several ER chaperone proteins, including protein disulfide isomerase. ER is responsible for protein folding, maturation, quality control and trafficking as well as cellular responses to stress and intracellular Ca2+ levels. If final tertiary structure cannot be achieved, misfolding proteins are then transported back to the cytosol and subjected to ubiquitination and proteasome-dependent degradation, a process referred to as ER-associated degradation. Imbalances between so-called client proteins cause the folding of proteins in the ER and apoptosis. A threat to equilibrium between the load of nascent synthesized client proteins and the capacity of ER is referred to as ER stress. When ER becomes stressed due to the accumulation of newly synthesized unfold proteins, it’s referred to as ER stress, which results in the activation of intracellular signal transduction pathways to restore normal ER function. This activation is called the unfolded protein response (UPR). Unfolded protein response is activated to decrease unfolded protein and to increase protein-folding capacity. The unfolded protein response is mediated by at least 3 transmembrane proteins, including inositol-requiring enzyme 1, protein-kinaseRNA like ER kinase and activating transcription factor 6 [43]. Alterations in calcium homeostasis and accumulation of unfolded proteins in the ER cause ER stress. Caspase-12 plays an essential role in the ER stress-induced apoptotic pathway. Activation of caspase 12 (caspase-4 in humans) by ER stress is mediated by calpain, which is activated by Ca2+ elevation. When unfolded proteins accumulate in the ER lumen, GRP78 releases the transmembrane ER proteins, allowing them to either dimerize or move to other locations within the cell, thereby initiatiating UPR to establishing homeostasis and normal ER function. Induction of UPR by ER stress occurs through three major transducers, RNA-dependent protein kinase-like ER kinase (PERK), activating transcription factor 6 (ATF6) and inositol-requiring ER-to-nucleus signal kinase 1 (IRE1). Activation of PERK leads to phosphorylation of eukaryotic translation initiation factor 2a (eIF2a), which causes general inhibition of protein synthesis. In response to ER stress, 90-Kda ATF6 (p50ATF6) transits to the Golgi

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complex where it is cleaved by site-1 protease (S1P) and site-2 protease (S2P), yielding an active transcription factor, 50 kDa ATF6 (p50ATF6). Similarly activated IRE1 catalyzes removal of a small intron from the messenger RNA (mRNA) of x-box binding protein 1 (XBP1). This splicing event creates a translational frameshift in XBP1 mRNA to produce an active transcription factor. Active p50ATF6 and XBP1 subsequently bind to the ER response stress element (ERSE) and the UPR element (UPRE), leading to the expression of target genes encoding ER chaperones and ERAD factors involved in degradation of unfolded proteins [44]. ERinduced apoptosis is mediated by several pathways that including CCAAT/Enhancer binding protein homologous protein mediated pathway, IRE1-mediated pathway, caspase-mediated pathway. ER stress plays a pathogenic role in diseases associated with the accumulation of misfolded proteins such as conformational diseases like Alzheimer’s disease, Parkinson&s disease, Huntington’s diseases. ER stress is also associated with ischemia/ reperfusion injury, diabetes and atherosclerosis. Megsin is a novel serpin (aggregated serine protease in the ER) that excessive production can overwhelm the protein-folding capacity of the ER and induce accumulation of misfolded megsin in turn leading to seringopathy associated with ER stress. ER stress-induced pathological diseases in kidney cause glomerular injury and tubulointerstitial injury. ER stress selectively impairs erythropoietin (EPO) production but not that of other hypoxia-inducible factor (HIF) target genes and modifies EPO 30 -enhancer activity by ATF4 binding to the enhancer region without interfering with HIF-2a directly. The UPR state, which maintains ER homeostasis, might play an important role in regulating the oxygen-sensing machinery for EPO transcription [45]. Furthermore, there is a link between oxidative stress and inflammations in pathological states are associated with ER stress. Hypoxia and ischemia are known ER stressors. An imbalance between protein load and folding capacity is referred to as endoplasmic reticulum stress. As a defense mechanism, cells express ER stress inducible chaperons such as oxygen-regulated proteins 150 (ORP150) and glucose regulated proteins (GRPs). In study by Inagi et al. investigated expression of ER stress proteins in cultured rat podocytes as animal model of abnormal protein retention within the ER of podocytes (megsin transgenic rat). The expression of ER stress inducible proteins (ORP150, GRP78 or GPR94) in cultured podocytes treated with tunicamycin, A23187, SNAP, hypoxia, or hyperglycemia and the renal tissues or isolated glomeruli from megsin transgenic rats was analyzed by western blotting analysis, immunohistochemistry, or confocal microscopy. Extracts of isolated glomeruli from megsin transgenic rats revealed marked up-regulation of ER stress chaperones in podocytes which was supported by immunohistochemical analysis. Confocal microscopy revealed that ER stress in podocytes was associated with cell injury. Podocytes of transgenic rats overexpressing a mutant megsin without the capacity for polymerization within the ER, do not exhibit ER stress or podocyte damage, suggesting a pathogenic role of ER retention of polymerized megsin. These findings implicated a crucial role of the accumulation of excessive proteins in the podocyte ER in the induction of ER stress and associated podocyte injury [46]. An original study by Ohse et al. investigated ER stress and ER stressinduced apoptosis in proximal tubule cells (PTCs). Immortalized rats PTCs (IRPTCs) were cultured with bovine serum albumine (BSA). The viability of IRPTCs decreased proportionately with BSA overload in a time-dependent manner. Quantitative real-time polymerase chain reaction analysis revealed that 40 mg/mL BSA increases mRNA of ER stress markers by 7.7- and 4.6-fold GRP78 and ORP150, respectively, as compared to control. These observations demonstrated that ER stress proteins were upregulated at PTCs in experimental proteinuric rat. Furthermore, increased ER stress-induced apoptosis and activation of caspase-12 were

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observed in IRPTCs with albumin overload and kidneys of experimental proteinuric rats. They confirmed that apoptotic cell death was attenuated by co-incubation with caspase-3 inhibitor or calpain inhibitors. These results indicate that the ER stress-induced apoptosis pathway contributed to the insult of tubular cells by proteinuria. Finally, renal tubular cells exposed to high protein load suffer from ER stress. ER stress may subsequently lead to tubular damage by activation of caspase-12 [47]. The ER is considered a key player in the response to cellular stress and protein overload of the ER. Lindenmeyer et al., in an original study, hypothesized that proteinuria and hyperglycemia in diabetic nephropathy (DN) may induce ER stress in tubular cells of the kidney. They investigated expression of genes involved in the ER response in diabetic nephropathy and minimal change disease. Gene expression was analyzed by microarray analysis and quantitative reverse transcriptase-PCR in the tubulointerstitial compartment of renal biopsies of patients with established, proteinuric DN and serum creatinin concentration  1.4 mg/dL and from biopsies with mild DN (i.e., serum creatinine < 1.4 mg/dL and only little histologic alteration of the interstitium). Expression UPR genes was significantly different in these biopsies than in control kidneys or biopsies of patients with mild diabetic nephropathy, suggesting an association between the degree of DN and UPR gene expression. Expression of the transcription factor XBP1 and the ER chaperones HSPA5 and HYOU1 were increased, but the proapoptotic gene DDIT3 was unchanged. Immunoflorescence of renal biopsies of renal biopsies from patients with DN confirmed the upregulation for HSPA5 and HYOU1 proteins in tubular epithelia. In biopsies of minimal change disease the mRNA levels of some ER stress molecules were also induced, but protein expression of HSPA5 and HYOU1 remained significantly lower than that observed in DN. Exposure of renal tubular epithelial cells to albumin and high glucose in vitro enhanced expression of genes involved in ER stress. These observations suggest that in proteinuric diseases tubular epithelial cells undergo ER stress, which induces an adaptive protective UPR. Although this may protect the cells from ER stress, persistence of hyperglycemia and proteinuria may eventually lead to apoptosis [48]. ER stress is associated with a range of diseases including ischemia/reperfusion injury, neuronal degeneration, and diabetes. In study by Inagi et al., investigated whether therapeutic approaches targeting ER stress might be effective against renal disease using an anti-Thy1 model of mesangioproliferative glomerulonephritis in rats. Immunohistochemistry and western blotting showed a time-dependent increase in the expression of the ER stress-inducible chaperones GRP78 and ORP150 in isolated glomeruli, especially in the glomerular epithelial cells and mesangial cells, after induction of anti-Thy1 nephritis. For evaluation of whether preconditioning with ER stress ameliorates the severity of disease, rats were pretreated with a subnephritogenic dose of the ER stress inducer tunicamycin or thapsigargin for 4 day before disease was induced. Although preconditioning with ER stress had no effect on the degree of disease induction, it strongly ameliorated the manifestations of disease, evidenced by marked reductions in microaneurysm formation, mesangial proliferation, and adhesion of bowman’s capsule to the glomerular tuft. This improvement in histologic damage was associated with reduced proteinuria (39.4–10.5 versus 126.1–18.1 mg/dL; P 0.01) and with attenuated increases in glucose-regulated protein 78 and oxygen-related protein 150 expressions. Of note, pretreatment with tunicamycin or thapsigargin decreased the excessive ER stress-induced intracellular signaling observed in anti-Thy1 nephritis. Anti-Thy1 nephritis is associated with ER stress and the subsequent induction of UPR for cell survival, such as an increase in the expression of ER chaperones GRP78 and ORP150, and activation of signal transduction pathways to shutdown

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translation. Preconditioning with ER stress ameliorated the severity of the manifestations of anti-Thy1 nephritis. These findings suggest the possibility of therapeutic approaches targeting ER stress in mesangioproliferative glomerulonephritis [49]. Paracetamol also known as acetaminophen is widely used as an analgesic and antipyretic drug. An acute paracetamol overdose can lead to potentially lethal liver and kidney injury in humans, experimental animals and in severe cases to death. Paracetamol has been shown that promote hepatocyte apoptosis. Studies in human hepatic cells have shown that paracetamolinduced apoptosis is caspase-dependent and that mitochondria are a primary target. Caspase-12 is specifically localized on the cytoplasmic side of the endoplasmic reticulum and connects ER stress to the caspase activation cascade. Because caspase-12 is expressed at high levels in the kidney and specifically in renal tubular epithelial cells, the cells affected during paracetamol nephrotoxicity. In a study, Lorz et al. investigated the ability of paracetamol to induce apoptosis of cultured mouse renal tubular epithelial cells and the participation of the death receptor Fas, ER stress and capsese in the process. The presented study showed that paracetamol induces apoptosis of cultural murine tubular epithelial cells through a caspase mediated mechanisms that involves caspase 9 and caspase-3 in a cytochrome C and Smac/DIBLOindependent manner. Caspase 12 has been reported to cleave caspase 9 in vitro in the absence of cytochrome C. This raises the possibility that caspase 12 is the apical caspase in paracetamolinduced apoptosis in tubular epithelial cells. Paracetamol causes ER stress in tubular cells, leading to GADD153 upregulation and translocation to the nucleus, as well as caspase-12 cleavage. These results suggest that induction of apoptosis may underlie the nephrotoxic potential of paracetamol and identify ER stress as a therapeutic target in nephrotoxicity [50]. ER is one of the largest cell organelles that are responsible for the production of cellular components, proteins, lipids, and sterols. Its proper function is essential for the cell. Various agents, including oxidants, can interfere with the ER function, leading to ER stress and cell death. Caspase 12 is an ER-specific caspase that is localized to the cytosolic face of the ER, making it vulnerable to the ER stress and the activation of the caspase cascade. In a study, Lui et al., cleavage of procaspase 12 preceded that of caspase 3 and 9 after cisplatin treatment of LLC-PK1 cells. The active form of caspase 8 was not detected throughout the course of study. Preincubation of the LLC-PK1 cells with the caspase 9 inhibitor did not attenuate caspase 3 activation and provided no significant protection. Caspase 3 inhibitor provided only modest protection against cisplatin-induced apoptosis. LLC-PK1 cells that were transfected with anti-caspase 12 antibody significantly attenuated cisplatin-induced apoptosis. Taken together, these data indicate that caspase 12 plays a pivotal role in cisplatin-induced apoptosis. It is proposed that the oxidative stress that results from the interaction of cisplatin with the ER cytochrome P450 leads to activation of procaspase 12, resulting in apoptosis [51]. Autophagy is closely interconnected with endoplasmic reticulum stress to counteract the possible injurious effects related with the impairment of protein folding. Studies have shown that glomerular podocytes exhibit high rate of autophagy to maintain as terminally differentiated cells. In a study Cheng et al., thapsigargin/ tunicamycin treatment induced a significant increase in endoplasmic reticulum stress and of cell death, represented by higher GADD153 and GRP78 expression and propidium iodide flow cytometry, respectively. However, thapsigargin/tunicamycin stimulation also enhanced autophagy development, demonstrated by monodansyl cadaverine assay and LC3 conversion. To evaluate the regulatory effects of autophagy on ER stress-induced cell death, rapamycin (Rap) or 3-methyladenine (3-MA) was added to enhance or inhibit autophagosome formation. Endoplasmic

reticulum stress-induced cell death was decreased at 6 hours, but was not reduced at 24 hours after rapamycin thapsigargin (RapTG) or rapamycin tunicamycin (RapTM) treatment. In contrast, ER stress-induced cell death increased at 6 and 24 hours after 3-MATG or 3-MATM treatment. This study demonstrated that thapsigargin/tunicamycin treatment induced endoplasmic reticulum stress, which resulted in podocytes death. Autophagy, which counteracted the induced endoplasmic reticulum stress, was simultaneously enhanced. The salvational role of autophagy was supported by adding Rap/3-MA to mechanistically regulate the expression of autophagy and autophagosome formation. They proposed that adequate, but not excessive, autophagy is crucial to help maintain the cell survival and viability of podocyte as a terminally differentiated cell lineage in glomerulus [52]. In an original study, Cummings investigated actions of oxidants on endoplasmic reticulum bound Ca2+ independent phospholipase A2 (ER-iPLA2) and phospholipids in renal cells. Exposure of renal tubule cells (RPTC) to the oxidants tert-butyl hydroperoxide (TBHP), cumene hydroperoxide, and cisplatin resulted in time and concentration dependent decreases in the activity of ER-iPLA2. TBHP-induced ER-iPLA2 inactivation was reversed by the addition of dithiothreitol to microsomes isolated from treated RPTC. TBHP also directly inactivated ER-iPLA2 in microsomes isolated from untreated RPTC. Similar to RPTC, dithiothreitol prevented TBHPinduced ER-iPLA2 inactivation in microsomes as did the reactive oxygen scavengers butylated hydroxytoluene and N, N’-diphenylp-phenylenediamine and the iron chelator deferoxamine. Electron paramagnetic resonance spin trapping demonstrated that TBHP initiated a carbon-centered radical after 1 min of exposure in microsomes, preceding ER-iPLA2 inactivation, and further studies suggested that the formation of the carbon-centered radical species occurred after or in concert with the formation of oxygencentered radicals. Phospholipid content was determined after TBHP exposure in the presence and absence of the ER-iPLA2 inhibitor bromoenol lactone. Treatment of RPTC with TBHP resulted in 35% decreases in (16:0, 20:4) – phosphatidylethanolamine (PtdEtn), (18:0, 18:1) – plasmenylethanolamine (PlsEtn), a 30% decrease in (16:0, 18:3) – phosphatidylcholine (PtdCho), and a 25% decrease in (16:0, 20:4) – phosphatidylcholine (PtdCho). In contrast, treatment of RPTC with bromoenol lactone before TBHP exposure decreased the content of 11 phospholipids, decreasing a majority of PlsEtn phospholipids 60%, and 4 of the 8 PlsCho phospholipids 40%, while PtdCho and PtdEtn were marginally affected compared with TBHP. These data demonstrate that ER-iPLA2 is inactivated by oxidants, which the mechanism of inactivation involves the oxidation of ER-iPLA2 sulfhydryl groups, and that ER-iPLA2 inhibition increases oxidantinduced RPTC phospholipid loss [53]. 3.4. Lysosome and kidney The lysosomes are generally believed to play a major role in the breakdown of intracellular proteins. Protein degradation by the lysosomal system involves sequestration of intracellular proteins in autophagic vacuoles, fusion of these vacuoles with primary lysosomes, and degradation of proteins within the lysosomes by proteases [54]. Cathepsins B and L are highly active lysosomal proteases. It has been shown that inhibition of these proteases also inhibits the intracellular protein degradation by up to 70%. The aminoglycoside antibiotic, gentamicin, is nephrotoxic in man and experimental animals. Uptake occurs in the proximal convoluted tubule predominantly via the luminal cell surface. Gentamicin is incorporated into proximal tubule lysosomes after attachment to luminal surface receptors and endocytosis. It accumulates in the lysosomes, and the renal cortical tissue half-life is approximately 100 hours. Morphologic alterations in gentamicin nephrotoxicity

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are present predominantly in the proximal tubule. Due to the accumulation in the proximal tubule lysosomes, impaired function of these organelles may be an important mechanism leading to proximal tubular toxicity. When the concentration of aminoglycoside in endosomal structures exceeds an undetermined threshold, their membrane is disrupted and their content, along with the drug, is poured into the cytosol. Cytosolic gentamicin then acts on mitochondria directly and indirectly, and thus activates the intrinsic pathway of apoptosis, interrupts the respiratory chain, impairs ATP production, and produces oxidative stress by increasing superoxide anions and hydroxyl radicals, which further contributes to cell death. The indirect mitochondrial effect is mediated by increasing Bax (Bcl-2-associated x protein) levels through the inhibition of its proteosomal degradation. In addition, the lysosomal content bears highly active proteases named cathepsins, which are capable of producing cell death. Cathepsin-mediated cell death occurs through apoptosis by directly cleaving active executioner caspases and indirectly unleashing the intrinsic pathway through the proteolytic activation of Bid (Fig. 3). Olbricht et al. investigated the effect of gentamicin on lysosomal function. Activity of the key lysosomal proteinases, cathepsins B and L, microdissected S1, S2, and S3 segments of rat proximal tubules by means of a fluorometric microassay. The catapsin activities were decreased in S1 and S2 following one and four

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gentamicin injections of 100 mg/kg body weight. Lysosomal enzyme of acid phosphatase was not decreased by gentamicin but the urinary excretion of catapsin L and B was decreased. In vitro incubation of urine and tubule segments with gentamicin demonstrated a concentration-dependent reversible inhibition of cathapsins in B and L. They concluded that gentamicin per se decreased cathepsin B and L activities in proximal tubule segments as early as 24 hours following one injection due to either enzyme inhibition or reduced generation of active intralysosomal cathepsin B and L. Gentamicin may, therefore, reduce renal protein catabolism by decreasing the activity of the key proteolytic enzymes, cathepsin B and L. Since cathepsin B and L are proteolytic activators of other lysosomal enzymes, their reduced activity may also decrease the activities of other lysosomal enzymes [55]. In a study, Sandoval et al. investigated the aminoglycoside trafficking from the Golgi complex to other intracellular organelles could serve as the rout of transport allowing for direct organelle delivery and subsequent toxicity. Utilization of this pathway would keep aminioglycosides within the vesicular compartment and is consistent with the lack of directly observable free cytosolic aminoglycoside. A well characterized fluorescent gentamicin marker colocalized with both endosomal/lysosomal vesicles and with the Golgi complex, concurrent with inhibition of protein synthesis. This represents the first documentation of aminogly-

Fig. 3. Cellular mechanisms of cytotoxicity of gentamicin. Gentamicin occurs in those cell types in which the drug accumulates. In the kidneys, these cells constitute the epithelial cells in the cortex, mainly in the proximal tubule. ATP: adenosine triphosphate; C: cubilin; GC: Golgi complex; GEC: giant endocytic complex; ER: endoplasmic reticulum; Lys: lysosome; M: megalin; PL: phospholipids; ROS: reactive oxygen species.

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cosides trafficking to the Golgi complex [56]. Ling et al., in the study, demonstrated that ammonium chloride (NH4Cl) induces hypertrophy but not hyperplasia in cultured rat mesangial cells. Cell hypertrophy is caused by the reduction of protein degradation, mainly due to depressed activities of cathepsins B and L + B, without enhanced protein synthesis. In contrast to cathepsins + L, the activity of cathapsin H did not decline after exposure of the mesangial cells to NH4Cl. Furthermore, preincubation of cell lysates in different pH buffers revealed even a rise of cathepsin H activity at a relative high pH. This finding is a line with earlier studies indicating that the optimal pH of cathepsin H is higher than that of cathepsins B and B + L in the lysosomes. Intralysosomal alkalization seems to be implicated in the depressed cathepsins B and L + B activities and the consequent impairment of protein breakdown [57]. Cholesterol originates from the endoplasmic reticulum (ER) via biosynthesis and the lysosome via import of exogenous cholesterol. The lysosomal-peroxisome contact site also requires to mentioning Niemann-Pick disease type C (NPC1) suggesting that this contact is important for cholesterol exit from the lysosome. In addition to specialized functions including calcium homeostasis and storage, intracellular signaling, organelle division, and lipid biosynthesis; membrane contact sites have repeatedly been shown to facilitate lipid transfer between membranes. It is tempting to speculate that interorganelle contacts are the major routes of lipid transfer between cellular compartments and fundamental to the accurate distribution of distinct lipids species throughout the cell [58]. Albumin molecules are taken up into lysosomes in the proximal tubules within six to fifteen minutes and the degraded into amino acids after 30–120 min in the proximal tubule. In subjects with nephrotic syndrome, tubular reabsorption of proteins is increased up to 13 times and lysosomal proteolysis enzymes are enhanced up to 8 times that observed in controls. However, the capacity for tubular reabsorption of albumin is approximately 30 g per day; therefore the remaining glomerular filtered albumin is excreted in the urine. Tubules overloaded with proteins produce pro-inflammatory cytokines, causing tubulointerstitial damage [59]. During progression of proteinuria and kidney injury, the accumulations of certain proteins in the lysosomes of the proximal tubules are thought, via mediators, to induce inflammation and fibrogenesis in the interstitium. Filtered albumin is mainly reabsorbed from the proximal tubule lumen by receptor-mediated endocytosis. There are three endocytic pathways involved in receptor-mediated endocytosis with respect to vesicle formation:  endocytosis via clathrin-coated pits;  caveolae-mediated endocytosis;  clathrin – and caveolae – independent endocytosis by a largely unknown mechanism. Megalin and cubilin are the major scavenger receptors for physiologic reabsorption of filtered albumin by proximal tubular cells. The megalin-cubilin complex accepts a variety of ligands including albumin, vitamin binding proteins, hormone binding proteins, hormones, and light chains. Kidney injury molecule-1 (KIM-1) is a scavenger receptor that is upregulated on the apical membrane of proximal tubules in proteinuric kidney disease. It is of importance that KIM-1 enhances albumin uptake and delivery to the lysosomes as many reports have validated changes in the levels of different inflammatory proteins and transcription factors in response to protein load and lysosomal protein accumulation in the proximal tubule. The nephrotoxicity of albuminuric states may be not only due to the protein molecule itself but that the toxicity resides in lipid carried on albumin. Therefore, a new functional role of tubular KIM-1 was identified as an enhancer of luminal albumin trafficking under proteinuric conditions. KIM-1-induced albumin

uptake was mediated by clathrin-dependent endocytic pathway, since albumin accumulation was effectively inhibited by chlorpromazine. Furthermore, because albumin by itself stimulates KIM-1 expression in cultured renal tubule epithelial cells (TECs), it is speculated that uptake of albumin would be increased, with great potential to accelerate renal injury induced by protein overload [60]. Furthermore, results of a study indicate that overloading of urinary proteins caused lysosomal membrane permeabilization (LMP) and lysosomal dysfunction at least partly via oxidative stress in TECs [61]. In a study, Carson et al. suggested lysosomes are involved in the processing of endocytosed albumin in the podocytes, and lysosomal dysfunction may contribute to podocyte injury and glomerulosclerosis in albuminuric diseases [62]. An original study suggests that megalin-cubilin and lysosomal rupture are involved in albumin-triggered tubular injury and tubulointerstitium [63]. 4. Conclusion Various intracellular organelles including mitochondria, peroxisomes, lysosomes, endoplasmic reticulum, and other subcellular organelles have critical functions. In addition to organelle-toorganelle communication within the cell, autocrine, paracrine and even endocrine mechanisms can be conveyed through cell-derived vesicles such as microparticles and exosomes. A defect in any of the components of this network leads to a serious pathological state of mitochondrial, lysosomal or peroxisomal diseases. Overally, organellar dysfunction involve in acute kidney injury, chronic kidney disease progression, metabolic syndrome, cardiovascular disease and cancer. Future development focusing on intraorganellar signaling in human clinical research is needed. Disclosure of grants or other funding No financial disclosure. Disclosure of interest The author declares that he has no competing interest. Acknowledgement None. References [1] Dhaunsi GS. Molecular mechanisms of organell biogenesis and related metabolic diseases. Med Princt Pract 2005;14(suppl 1):49–57. [2] Eguchi S, Rizzo V. Organells in health and diseases. Clin Sci 2016;131:1–2. [3] De Cavanagh EMV, Inserra F, Ferder M, Ferder L. From mitochondria to disease: role of the renin-angiotensin system. Am J Nephrol 2007;27:545–53. [4] Picard M, Wallace DC, Burelle Y. The rise of mitochondria in medicine. Mitochondrion 2016;30:105–16. [5] Weinberg JM. Mitochondrial biogenesis in kidney disease. J Am Soc Nephrol 2011;22:431–6. [6] Jain IH, Zazzeron L, Goli R, Alexa K, Schatzman-Bone S, Dhillon H, et al. Hypoxia as a therapy for mitochondrial disease. Sci 2016;352:54–61. [7] Hall AM, Unwin RJ. The not so mighty chondrion emergence of renal diseases due to mitochondrial dysfunction. Nephron Physiol 2007;105:1–10. [8] Perico L, Morigi M, Benigni A. Mitochondrial sirtuin 3 and renal diseases. Nephron 2016;134:14–9. [9] Small DM, Coombes JS, Bennett N, Johnson DW, Gobe GC. Oxidative stress, anti-oxidant therapies and chronic kidney disease. Nephrol 2012;17:311–21. [10] Granato S, Zaza G, Simone S, Villani G, Latorre D, Pontrelli P, et al. Mitochondrial dysregulation and oxidative stress in patients with chronic kidney disease. BMC Genomics 2009;10:1–13. [11] Che R, Yuan Y, Huang S, Zhang A. Mitochondrial dysfunction in the pathophysiology of renal diseases. Am J Physiol Renal Physiol 2014;306:367–78. [12] Granata S, Gassa AD, Tomei P, Zaza G. Mitochondria: a new therapeutic target in chronic kidney disease. Nutr Metab 2015;12:49.

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Please cite this article in press as: Shamekhi F. Intracellular organelles in health and kidney disease. Ne´phrol ther (2018), https://doi.org/ 10.1016/j.nephro.2018.04.002