Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets

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Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locat e/dia bre s

Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets Dilip Sharma, Pallab Bhattacharya, Kiran Kalia *, Vinod Tiwari * Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar 382355, Gujarat, India

A R T I C L E I N F O

A B S T R A C T

Article history:

Diabetic nephropathy is one of the most prevalent microvascular complication in patients

Received 21 January 2017

suffering from diabetes and is reported to be the major cause of renal failure when com-

Accepted 7 April 2017

pared to any other kidney disease. Currently, available therapies provide only symptomatic

Available online 13 April 2017

relief and unable to treat the underlying pathophysiology of diabetic nephropathy. This review will explore new insights into the established therapeutic paradigms targeting

Keywords: Diabetic nephropathy Endothelin Epigenetics Inflammation Micro-RNA Wnt signaling

oxidative stress, inflammation and endoplasmic reticulum stress with the focus on recent clinical developments. Apart from this, the involvement of novel cellular and molecular mechanisms including the role of endothelin-receptor antagonists, Wnt signaling pathway, epigenetics and micro RNA is also discussed so that key molecular switches involved in the pathogenesis of diabetic nephropathy can be identified. Elucidating new molecular pathways will help in the development of novel therapeutics for the prevention and treatment of diabetic nephropathy. Ó 2017 Elsevier B.V. All rights reserved.

Contents 1. 2.

3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-inflammatory drugs as therapeutics against diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Cyclooxygenase (COX) and xanthine oxidase (XO) inhibitors in diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . 2.2. Monocyte-chemoattractant protein-1 (MCP-1) inhibitors and diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . 2.3. Tumor necrosis factor-a (TNF-a) inhibitors and diabetic nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Nuclear factor-kappa b (NF-jb) signaling in diabetic nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of protein kinase C (PKC) in diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3-Hydroxy-3-methylglutanyl coenzyme a (HMG-CoA) reductase inhibitors and diabetic nephropathy . . . . . . . . . . . . . . Role of endothelin receptors in diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wnt signaling and diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Corresponding authors. Fax: +91 79 27401192. E-mail addresses: [email protected] (K. Kalia), [email protected], [email protected] (V. Tiwari). http://dx.doi.org/10.1016/j.diabres.2017.04.010 0168-8227/Ó 2017 Elsevier B.V. All rights reserved.

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Current status of antioxidants and endoplasmic reticulum (ER) stress inhibitors in diabetic nephropathy . . . . . . . . . . 99 7.1. Potential anti-oxidants against diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 7.2. Inhibitors of endoplasmic reticulum (ER) stress and diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Novel molecular targets in diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 8.1. MicroRNAs and diabetic nephropathy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 8.2. Epigenetical mechanisms involved in diabetic nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Introduction

Being the cause of nearly 1 in 5 deaths, diabetes is an extremely prevalent and most common non-communicable lifestyle disease. The population living with diabetes is expected to rise from 366 million to 552 million by 2030, including nearly 183 million people with undiagnosed diabetes for long duration [1–3]. These figures equate to about three new cases every ten seconds or almost ten million new cases reported per year. With approximately 61.3 million people living with diabetes, India is second to China on the global scale [4,5]. Diabetic nephropathy (DN) is a major microvascular complication that accounts for 30–47% cases of end-stage renal disorders. Different factors involved in end-stage renal disease (ESRD) includes hemodynamic changes, inflammation, and hyperglycemia [6]. Initial stages of DN are characterized by lower amounts of proteinuria or microalbuminuria (albumin excretion of 30–299 mg/24 h), if unchecked, microalbuminuria progresses to an extensive proteinuria >500 mg in 24 h and manifests DN [7]. Mechanisms involved in development and progression of DN are still unclear. However, many researchers have shown a correlation between the degree of hyperglycemia and progression of DN complications. Moreover, better control over the glycemic state is associated with a decrease in the rate of progression of diabetic kidney disease and improvement of kidney functions in diabetic patients [8]. Besides this, tight glucose control is not the only way to control diabetic complication because even after that, diabetic patients continue to develop nephropathy and other vascular complications and metabolic memory is suggested to play an important role in this [9]. Metabolic memory is a term that has been used to define the process of remembering the prior hyperglycemic environment even after the establishment of normoglycemia [10]. The idea of metabolic memory first came into the frame from Diabetes Complications and Control Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) trial. The clinical trial was started with an objective of comparison between intensive insulin therapy and conventional insulin therapy. Findings suggested that mechanisms involved in hyperglycemic metabolic memory were non-enzymatic glycation of cellular proteins and lipids along with increased levels of reactive oxygen and nitrogen species and epigenetical changes. Several other researchers independently reported other mechanisms involved such as nuclear factor kappa beta (NF-kb)

and activation of caspase-3 in diabetes associated complications by virtue of metabolic memory [11]. Prolonged hyperglycemia-induce chronic metabolic and hemodynamic changes which modulates various intracellular signaling pathways, transcription factors, cytokines, chemokines, and growth factors. Collectively, these changes stimulate structural abnormalities such as glomerular basement membrane thickening, podocyte injury and mesangial matrix expansion along with reduced glomerular filtration rate leading to the occurrence of glomerular sclerosis and tubule-interstitial fibrosis [12]. Various research groups have reported a myriad of molecular pathways which may be involved in the development and progression of diabetic nephropathy. These pathways include the activation of protein kinase C (PKC), increased oxidative stress, enhanced flux into the polyol and hexosamine pathways and increased transforming growth factor b (TGFb). Other pathways involved are activation of mitogen-activated protein kinase (MAPK), increased formation of advanced glycation end products (AGEs), activation of endothelin receptors, Wnt signaling and epigenetical mechanisms [13]. Experiments on mesangial cells, endothelial cells and podocytes of the kidney showed hyperglycemia-mediated activation of these critical pathways [14]. The prevention and management of diabetic nephropathy should be multi-targeted, advocating a healthy lifestyle and targeting cellular and molecular switches involved in pathogenesis of same. The goal of the management is to reduce the risk of renal disease progression, as well as the risk of cardiovascular morbidities. In this review we have discussed new insights into the established therapeutic paradigms with a focus on recent clinical developments. Apart from this, we have also discussed novel cellular and molecular mechanisms associated with pathological changes during the development and progression of diabetic nephropathy.

2. Anti-inflammatory drugs as therapeutics against diabetic nephropathy Diabetic nephropathy involves activation of chronic inflammatory cascade and enhanced immune response [15]. Development of diabetic nephropathy is associated with significant inflammatory cells infiltration along with an increase in plasma levels of C-reactive protein (CRP) and proinflammatory cytokines such as vascular cell adhesion molecule-1 (VCAM-1), interleukins (IL-1, IL-6, and IL-18) and tumor necrosis factor-a (TNF-a) [16]. Transcription factors such as NF-jb, upstream stimulatory factor (USF) 1 and 2,

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Fig. 1 – Role of COX and PGE2 in diabetic nephropathy. Production of prostaglandin is initiated by COX enzymes which lead to progression of diabetic nephropathy by inducing inflammation, fibrosis and alterations of hemodynamic factors. PLA2: Phospholipase A2; PGE2: Prostaglandin E2; COX-1 and COX-2: Cyclooxygenase-1 and 2; EP receptors: Prostaglandin E2 receptors.

nuclear factor of activated T-cells (NFAT), stimulating protein 1 (Sp1) and cAMP-response-element-binding protein (CREB) are stimulated by hyperglycemic environments [17]. NF-jb plays a prominent role in the pathogenesis and progression of diabetic nephropathy and is stimulated by many types of stimuli such as reactive oxygen species or oxygen free radical, cytokines and viral products [18]. Intracellular adhesion molecule-1 (ICAM-1) and VCAM-1 are synthesized by glomerulus endothelial cells, mesangial cells and renal tubular epithelial cells and known to be elevated during diabetic nephropathy [19,20]. Clausen et al. (2000) found elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (sICAM)-1 in patients suffering from Type 1 diabetes mellitus with microalbuminuria and nephropathy. AGEs are another key factor that binds to a receptor of RAGE and high expression of AGE/RAGE interactions have been reported in the progression of diabetic nephropathy [21]. Now, the question arises, whether anti-inflammatory drugs may protect the kidney against diabetes or not? However, this question is not new, the renoprotective effects of non-steroidal anti-inflammatory drugs (NSAIDs) were assessed in diabetic patients more than 30 years ago itself. Findings from the study suggest that indomethacin treatment significantly decreased serum creatinine and chronic dialysis in patients suffering from diabetic nephropathy [22,23]. Limitation of this study was whether anti-inflammatory activity of

the indomethacin was responsible for the alleged long-term renoprotective effects could not be determined because specific assays such as ELISA for determination of inflammatory markers were not available at that time. With the help of more advanced techniques, many novel inflammatory components have been discovered in patients suffering from diabetic nephropathy which has spurred scientists to develop new drugs against them.

2.1. Cyclooxygenase (COX) and xanthine oxidase (XO) inhibitors in diabetic nephropathy COX is a key enzyme involved in prostaglandin (PG) synthesis from arachidonic acid in the body [24]. Various types of cells present in different parts of kidney express high levels of COX enzymes. Both the subclasses, COX-1 and COX-2 are known to be expressed with the predominance of COX-2 in tissues such as macula densa and thick ascending limb [25]. All renal cells can synthesize PGE2, with highest production rates seen in the collecting ducts and glomeruli; this leads to activation of renin release, glomerular filtration and activation of prostanoid (EP) receptors [26]. By acting on four classes of EP receptors PGE2 is reported to be involved in regulation of various processes in progression of kidney diseases as depicted in Fig. 1. Researchers have evaluated effect of PGE2 in regulating diabetic nephropathy in various pre-clinical models. Makino et al. (2002) used selective antagonist of the

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PGE receptor EP1, ONO-8713 and compared its effect with non-selective PGE synthase inhibitor, aspirin in streptozotocin (STZ)-induced diabetic rat model. Findings from this study suggests that both the selective and non-selective inhibitors attenuate mesangial expansion but glomerular hypertrophy and proteinuria were inhibited only by treatment with selective inhibitor of PGE receptor [27]. These findings suggest that, PGE2 along with COX can provide us with promising targets for kidney diseases owing to their effect on various parameters associated with diabetic nephropathy such as hyperglycemia, hypertension, inflammation and oxidative stress [28]. Development and progression of diabetic nephropathy is associated with an increase in the COX-2 expression in podocyte cells of kidney [29]. Non-specific COX inhibitors such as aspirin and specific COX-2 inhibitors reduce glomerular injury, pro-fibrotic cytokines, proteinuria and increase renal hemodynamics in preclinical models of diabetes [30]. Recently a few drugs working as different enzyme inhibitor such as purine xanthine oxidase (XO) can be used to prevent oxidative stress and inflammation in diabetic nephropathy [31]. Febuxostat, a specific inhibitor of XO, has recently been shown to be effective in the treatment of hyperuricemia (increased uric acid in serum) [32]. Hyperuricemia is a risk factor involved in elevated diabetic nephropathy and other kidney diseases development [33]. Pre-clinical studies have reported that XO and COX-2 play a significant role in the pathogenesis of diabetic nephropathy and can be treated by XO inhibitors. In one pre-clinical study; type 2 diabetes was developed in Zucker obese rats and these animals were treated for 18 weeks with Febuxostat. XO inhibitors normalized serum uric acid and attenuated renal structure change, albuminuria, renal protein expression collagen 4, TGF-b, connective tissue growth factor more efficiently [34]. In addition to this, XO inhibitors also known to enhance the action of other drugs such as ACE inhibitors [35]. These studies suggest that along with COX inhibitors, XO inhibitors should be further explored owing to their possible protective action against diabetic nephropathy.

2.2. Monocyte-chemoattractant inhibitors and diabetic nephropathy

protein-1

(MCP-1)

MCP-1 promotes monocyte and macrophages activation and infiltration into glomeruli which in turn is linked to increased expression of adhesion molecules, and other proinflammatory cytokines and glomerular injury [36]. MCP-1 is produced by various types of renal cells, including podocytes, mesangial cells, tubular cells and monocyte-macrophages [37]. Moreover, patients suffering from type-II diabetes and nephropathy excrete high levels of MCP-1 in urine [38]. Recently, MCP-1 inhibitors such as breviscapine, triptolide, and other anti-diabetic drugs found to protect against DN by blocking MCP-1 receptor in animal models. Breviscapine treatment significantly attenuated nephropathy by inhibiting MCP-1 and PKC activities, and attenuating oxidative stress, TGFb1, and renal fibrosis via phosphorylation of p38, Akt, JNK1/2 and PKCbII [39]. Triptolide is another MCP-1 inhibitor which was found to be beneficial in a pre-clinical model of type-II diabetes. Triptolide attenuated diabetic nephropathy

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by decreasing inflammation and podocyte injury in rat model of diabetic nephropathy [40]. Triptolide was found to regulate the proportion of Th1/Th2 cells, reduced MCP-1 expression, macrophage infiltration as well as expression of related inflammatory factors in the kidney [41]. These preclinical findings suggest that MCP-1 inhibitors holds a potential for the treatment of diabetic nephropathy and needs to be further explored. In a randomized, double-blind, placebo-controlled Phase IIa study in 75 albuminuric type 2 diabetics, emapticap, a direct inhibitor of monocyte chemotactic protein-1 (MCP-1), reduced urinary albumin/creatinine ratio pointing towards its possible renoprotective effects [42]. Another interesting findings were recently mentioned by Brosius et al. (2016), where baricitinib, an inhibitor of Janus kinase-signaling pathway dose-dependently decreased albuminuria in patients suffering from diabetes. Although these studies supports the hypothesis that antiinflammatory strategies targeting the MCP-1 or the JAK–STAT pathway may be beneficial in preventing diabetic nephropathy, but there are many questions which still needs further scientific exploration. In most of the preclinical and clinical studies albuminuria is considered as the major biomarker for the disease progression and prevention. The very first question which should be raised whether albuminuria is the right surrogate marker to determine the efficacy of antiinflammatory drug treatment. It is quite possible that there are other more specific inflammatory markers which may serve as a better surrogate measure to determine drug efficacy. Moreover, it is also quite possible that antiinflammatory drugs may provide renoprotection without affecting albuminuria. Therefore, more research data is required to identify the right surrogate markers for antiinflammatory drug efficacy. Another important question which is also least explored is what is the effect of long term anti-inflammatory drug treatment on renal structural features and pathology? In most of the reported clinical studies, follow-up period after cessation of anti-inflammatory drug treatment is too short to characterize the long-lasting effects on renal structural features and disease pathology. Additional long term follow studies involving more advanced imaging techniques will be helpful in improving our understanding on disease pathophysiology and drug efficacy.

2.3. Tumor necrosis factor-a (TNF-a) inhibitors and diabetic nephropathy TNF-a is an inflammatory cytokine synthesized primarily by monocytes, macrophages and T-cells. Intrinsic renal cells such as tubular epithelial cells, mesangial cells, glomerulus and endothelial cells are also able to synthesize it [43]. TNFa plays a key role in the pathogenesis and progression of renal damage in diabetic nephropathy. Multiple actions of TNF-a are mediated by specific cell surface receptors such as a myeloid cell type receptor (p75) and epithelial cell-type receptor (p55) [44]. TNF-a induces a number of signal transcription pathways which in turn starts expression of a variety of transcription factors, cell adhesion molecules, acute phase proteins, major histocompatibility complex proteins, cytokines,

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growth factor receptors and mediators of inflammatory processes [45]. In vitro studies reveals the presence of a significantly increased concentration of TNF-a in the supernatant of isolated glomeruli culture from many renal diseases such as nephrotoxic serum nephritis, rapidly progressive glomerulonephritis and experimental focal and segmental glomerulosclerosis [46]. TNF-a inhibitor SKF86002 significantly decrease glomerulus TNF-a production and improves renal function in diabetic nephropathy [47]. Pan et al. (1996) also suggests that pretreatment of animals with the cytokine inhibitor SKF86002 prevented drop in renal blood flow however, it did not affect glomerular synthesis of vasoconstrictor eicosanoids [48]. Pentoxifylline also leads to decreases in mRNA expression of TNF-a in the glomerulus and epithelial kidney cells of diabetics [49]. The combination of pentoxifylline with angiotensin converting enzyme inhibitors, AT1 receptor blockers reported to significantly decreases urinary albumin excretion in diabetic nephropathy [50]. Pentoxifylline a derivative of methylxanthine phosphodiesterase inhibitor with anti-inflammatory properties, significantly inhibits TNF-a gene transcription, reduces expression levels of mRNA encoded TNF-a and may play important role in renoprotection in patients with diabetic nephropathy. Prospective, multicenter and a randomized double-blind clinical study were conducted in 174 patients (103 males, 71 females) with diabetes having albumin to creatinine ratio of (albuminuria; >30 mg/g of creatinine). Patients in the pentox-

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ifylline group received 1200 mg of pentoxifylline daily (400 mg dosage three times in a day; n = 87) for 6 months, whereas the placebo group (n = 87) received equal starch tablets on the same schedule. Pentoxifylline treated group was found to have percentage decrease of 23% (proteinuria) as compared to baseline and placebo group. In addition other effects of pentoxifylline such as reductions in glycosylated hemoglobin, fasting plasma glucose and renal function was significantly improved in comparison to placebo group [51].

2.4. Nuclear factor-kappa b (NF-jb) signaling in diabetic nephropathy NF-jb is induced by a wide variety of cellular response to stimuli including hyperglycemia, obesity, growth factor, increase plasma free fatty acid, cellular ligands, hypertension, cytokines and bacteria that plays an important role in the development of diabetic nephropathy [52]. Increased expression of NF-jb is observed in proximal tubular cells, glomerular endothelial cells and podocytes in the kidney of the diabetic patients [53]. Various types of receptors present on cell surface such as toll-like receptors (TLRs), respond to extracellular signals like hyperglycemia, oxidative stress, and inflammatory mediators [54]. These upon stimulation by extracellular signals activate iKB kinase which in turn lead to phosphorylation of NF-kb present in complex inactive form with iKBa. Upon phosphorylation, this complex dissociates to make active form of NF-kb along with degradation of

Fig. 2 – Hyperglycemia induced activation of NF-kb signaling. Extracellular signals like hyperglycemia activate iKB kinase via TLRs and converts inactive form of NF-kb to active form. Activated NF-kb leads to generation of pro-inflammatory genes and cytokines causing renal apoptosis. TLRs: Toll-like receptors; MCP-1: Monocyte-chemoattractant protein-1; IL-6: Interleukin-6; NF-kb: Nuclear factor-kb.

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phosphorylated iKBa. Activated NF-kb enters the nucleus and activates pro-inflammatory genes and cytokines such as MCP-1, IL-6 and leads to renal apoptosis [55]. NF-kb also leads to mesangial cell fibrosis by activating cell adhesion molecules such as ICAM, VCAM [56] (Fig. 2). Inhibitors of NF-jB have been used for amelioration of diabetic nephropathy, improvement of kidney function and reduced renal injury by inflammation [57]. Thiazolidinedione (PPAR-c agonist) treatment leads to improvement in renal injury in the experimental model of diabetic nephropathy by inhibiting NF-kb activity [58]. Other inhibitors of NF-jB such as an ellagic acid (2, 3, 7, 8-tetrahydroxy chromeno [5, 4, 3-cde] chromene-5, 10-dione) that is present in many fruits and plant extracts also known to improve kidney function [59]. Thus, drugs targeting NF-jB selectively holds a potential for the treatment of diabetic nephropathy and other kidney disorders.

3. Role of protein kinase C (PKC) in diabetic nephropathy Protein Kinase C (PKC) is a group of serine or threonine kinase enzyme consisting of 12 isoforms which has been reported to

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be associated in the progression and pathogenesis of diabetic nephropathy [60]. PKC plays an important role in several cellular functions and signals transduction pathways as shown in Fig. 3. Based on their regulatory domains these isoforms are classified into three subgroups as conventional (PKC isoforms a, b I/II and c), a novel (PKC isoforms d, e, g and h) and atypical (PKC isoforms f and i/k). These conventional, novels and atypical isoforms are regulated by calcium + Diacylglycerol (DAG), DAG alone and non-calcium-/non-DAG mechanisms respectively [61,62]. PKC activation is known to be associated with progression and pathogenesis of diabetic nephropathy. Hyperglycemia leads to PKC activation along with other stimuli such as including reactive oxygen species, AGE receptors, advanced glycation end products (AGEs) and angiotensin-II in diabetic nephropathy condition [63]. The pathway initiates with the conversion of glucose to DAG which activates PKC kinase which in turn increases TNF-b1 mRNA expression, activation of NADPH oxidase and altered vasomotor tone (PGE2/PGI2 or NO) [64]. TNF-b1 leads to increases in tissue fibrosis (mesangial expansion), basement membrane thickening, hemodynamic alterations and increase reactive oxygen species; all these factors leads to renal injury and diabetic nephropathy

Fig. 3 – Role of protein kinase C in hyperglycemia-induced diabetic nephropathy. Hyperglycemia leads to activation of protein kinase C by inducing AGEs, ROS, angiotensin–II and diacylglycerol (DAG). These pathways alters the normal physiology of kidney and results in diabetic nephropathy. AGEs: Advanced glycation end products; DAG: Diacylglycerol; ROS: Reactive oxygen species; TGF-b: Transforming growth factor-b; CTGF: Connective tissue growth factor; VEGF: Vascular endothelial growth factor; PGE2/PGI2: Prostaglandins E2/I2; NO: Nitric oxide; NADPH: Nicotinamide adenine dinucleotide phosphateoxidase.

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[65]. Thus, PKC inhibitors have the potential for treatment of diabetic nephropathy but owing to their non-selective action, it may lead to potential toxicity. Therefore, selective PKC inhibitors are preferred over non-selective ones. A randomized, double blind, clinical trials study was conducted to evaluate the effectiveness of ruboxistaurin in diabetic nephropathy patients. The study involves 123 diabetic subjects with persistent albuminuria and compared ruboxistaurin (32 mg/day) with placebo [66]. After one year, estimation of key parameters of diabetic nephropathy such as albumin/creatinine ratio and glomerulus filtration rate (GFR) was done. Patients receiving ruboxistaurin showed reduction of albumin to creatinine ratio up to 24 ± 9% which was much higher than placebo groups (9 ± 11%). Study concluded that decrease in albumin to creatinine ratio and glomerulus filtration rate was significant in active drug group (61 patients) and placebo group (63 patients) respectively but didn’t find any statistically significant difference between intergroups (placebo and ruboxistaurin) [63]. In an another study, JTT-010 was found to ameliorate the symptoms associated with diabetic neuropathy [61,67]. Thus, selective PKC-b inhibitors (ruboxistaurin and JTT-010) should be explored further for the prevention and reversal of diabetic nephropathy.

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4. 3-Hydroxy-3-methylglutanyl coenzyme a (HMG-CoA) reductase inhibitors and diabetic nephropathy HMG-CoA reductase inhibitors (statins) inhibit mevalonate synthesis step in cholesterol biosynthesis that is useful in the treatment of hyperlipidemia or hypercholesterolemia [68]. These have been proposed to be protective to endothelial cells and also having anti-inflammatory actions that are completely distinct from their hyperlipidemic or cholesterol-lowering effects. Whether statins are beneficial in improving renal functions in diabetic nephropathy is still controversial, but if they are involved, they might be working through inhibition of renal injury induced inflammation and endothelial dysfunction [69]. Statins are reported to ameliorate renal dysfunction and reduce renal injury by reducing inflammatory markers, adhesion molecules, NF-kb, macrophage infiltration, and activating protein-1 (AP-1); effects which are independent of its hyperlipidemic action [70]. However, use of HMG-CoA reductase inhibitors (statins) in the treatment of diabetic nephropathy is still questionable due to their conflicting effects. Recent findings suggest that statins can be used to treat diabetic nephropathy due to their anti-oxidant, anti-inflammatory, dyslipidemia and lipid-lowering potential [71] as described in Fig. 4.

Fig. 4 – Role of inflammatory cascade and its inhibition by 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors in diabetic nephropathy. HMG-COA reductase inhibitors (statins) are known to inhibit synthesis of isoprenoids (farnesyl pyrophosphate and geranylgeranyl pyrophosphate) which further leads to attenuation of Ras, Rac and Rho GTPases activity. These factors are involved in the activation of oxidative stress and other inflammatory mediators (PAI-1, ECM and eNOS) in kidney which finally leads to kidney damage. ECM: Extracellular matrix; PAI-1: Plasminogen activator inhibitor-1; eNOS: Endothelial nitric oxide synthase.

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Contrary to this, some studies have claimed that statins are not good candidates for the treatment of diabetes or diabetic nephropathy because of their side effects on the pancreas or diabetogenic properties [72]. Regulatory authority FDA in 2012 has given a statement on the use of statins and advised to add ‘‘reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels” to statin labels until the molecular mechanisms behind these remain unclear [73]. In another study, simvastatin was found to decrease glucosestimulated insulin secretion (GSIS) from mouse pancreatic b-cells (MIN6). Simvastatin treatment leads to decrease in insulin secretion from pancreatic b-cells by affecting ATPsensitive potassium channels and voltage-gated calcium channels [74,75]. It also inhibits direct activation of cAMPdependent signaling pathways through stimulation of G-protein coupled receptor-119 (GPR119), glucagon like peptide-1 (GLP-1), G-protein coupled receptor-40 (GPR40) and muscarinic M3 receptors agonists leading to decreased insulin secretion [76]. Another statin (atorvastatin) also found to be associated with an elevated risk of diabetes mellitus but the mechanism involved is different from simvastatin. In an in vitro study atorvastatin has shown to be associated with increased risk of diabetes due to mitochondrial apoptosis in the pancreatic cells [77]. A randomized, double-blind and controlled clinical trial of statins was performed to study the effectiveness of statins treatment in reducing diabetic nephropathy, findings suggest controversial or debated results. The study involved 130 patients with the glomerular filtration rate of 48.5 ± 16 mL/ minute/1.73 m2. Patients in the atorvastatin group received 80 mg dose daily for 48 h or placebo. Glomerular filtration rate and serum creatinine were measured before the intervention, 3 days and 10 days after intervention. In atorvastatin-treated group, mean serum creatinine level did not rise significantly on the third day and a decrease was observed up to baseline level or close to baseline on the tenth day suggesting a decline incidence of nephropathy in diabetic patients suffering from chronic kidney disease [78]. Thus, owing to the disparity in existing literature, it is difficult to conclude at this stage about the future of HMG-CoA reductase inhibitors in the treatment of diabetic nephropathy and more studies are required to support the either claims.

5. Role of endothelin receptors in diabetic nephropathy The endothelin (ET) family consists of three peptides; ET-1, ET-2, and ET-3 and all of them exerts their pharmacological actions via ETA and ETB2 receptors. ET plays a very important role in regulating the renal functions and injury. Kidneys are 10-fold times more sensitive to ET than to any other organs [79] as ET-1 is largely distributed in the renal microvasculature, in glomerular cells, and in the tubules. Endothelinreceptor antagonists may prove to be the potential therapeutics against diabetic nephropathy as involvement of endothelin-receptor has been strongly implicated in the pathogenesis and progression of numerous chronic kidney disease (CKD), reduced renal mass, glomerulonephritis,

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including diabetic nephropathy in various pre-clinical and clinical models [80]. More specifically, ET-1 peptide widely contributes to several different mechanisms causing kidney fibrosis, proteinuria and inflammation in chronic kidney disease and regulates numerous renal functions. Hyperglycemia, hypertensive glomerular injury, and insulin are responsible for the increase in the synthesis of ET-1 as well as can enhance its effectiveness [81]. Diabetic complications are known to be associated with abnormalities in ET system which may lead to damage in renal areas of microvasculature, podocytes, and mesangial cells. It is reported that antagonists of ET1 receptors can improve the physiology and functional outcomes in diabetic nephropathy [82]. Several clinical studies also supports the importance of ET system against diabetic nephropathy. Zeeuw et al. (2014) conducted randomized controlled trials in 211 diabetic nephropathic patients treated with ET antagonist, atrasentan at varying doses for 12 weeks. Findings suggest the overall improvement in diabetic nephropathy [83]. In another randomized controlled trial by Rafnsson et al. (2012), Bosentan, an ET antagonist was used against a small diabetic population of 56 patients. Oral treatment with bosentan, for 4 weeks improves peripheral endothelial function and microalbuminuria in patients with type 2 diabetes [84]. These findings suggest that endothelin receptor antagonist holds a strong potential and should be explored further for the treatment of patients suffering from diabetic nephropathy.

6.

Wnt signaling and diabetic nephropathy

Wnt signaling pathway has been implicated in multiple physiological and pathological processes including angiogenesis, inflammation and fibrosis of diabetic nephropathy [85]. Both the Wnt receptors and ligands are found to be up-regulated in diabetes and known to play a major role in podocyte dysfunction and renal fibrosis in diabetic nephropathy. Wnt works by binding with co-receptor complex made up of frizzled receptor and low-density lipoprotein receptor-related protein 5/6 and activates the transcription factor, b-catenin, known to be involved in activating transcription of Wnt genes responsible for angiogenesis, inflammation, and fibrosis in diabetic nephropathy [86]. Zhou et al. (2012) have evaluated the effect of blocking Wnt pathway in streptozotocin induced diabetic rats and db/db mice. Findings suggest that inhibition of Wnt pathway leads to improved proteinuria and decreased renal fibrosis in diabetic rodents [87]. In another study, authors have used adriamycin to induce Wnt signaling and activate b-catenin in mice podocytes. Results from this study suggests that activation of Wnt pathway aggravated albuminuria and leads to decrease in nephrin expression. Moreover, blocking of this pathway leads to improvement of podocyte lesions and reversal of nephropathy [88]. These findings suggests a pivotal role of Wnt/b-catenin pathway in diabetic nephropathy. However, further studies are required to identify the key molecular mechanisms involved so that novel therapeutics can be developed against this target for the protection of kidney damage.

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99

Fig. 5 – Metabolic pathways associated with diabetic nephropathy along with potential sites for therapeutic targeting. Increased hyperglycemia leads to activation of protein kinases, oxidative stress, AGEs and polyol pathway along with activation of ER stress pathway. This collectively leads to enhanced inflammatory signaling causing pathological and physiological alterations in renal tissues. PKC: Protein kinase C; AGEs: Advanced glycation end products; ATF6: Activating transcription factor 6, IRE1; Inositol-requiring enzyme 1; PERK: PKR-like eukaryotic initiation factor 2A kinase; GRP78/BiP: Glucose-regulated protein 78/immunoglobulin binding protein; NF-kB: Nuclear factor-kB; TNF-a: tumor necrosis factor-a; IL-6: interleukin-6; 4-PBA: 4-Phenylbutyric acid; ACEI: angiotensin-converting enzyme inhibitors; TGF-b: Transforming growth factor-b; VEGF: Vascular endothelial growth factor.

7. Current status of antioxidants and endoplasmic reticulum (ER) stress inhibitors in diabetic nephropathy It is well reported that oxidative stress induced by hyperglycemia reduces the secretion of insulin in pancreatic b-cells through the activation of multiple signaling pathways such as AGE as well as PKC-MAPK and decreases ATP/ADP ratio by leaking protons in the b-cell [89]. Endoplasmic reticulum (ER) is involved in lipid biosynthesis and protein packaging, and also act as intracellular calcium store and sensor of cellular stress [90]. Both the processes are depicted in Fig. 5. The key role of ER is related to folding, modification, degradation and trafficking of transmembrane and secretory proteins. ER stress induced by a stressful stimuli such as hypoxia and inflammation disturbs the capacity of ER for protein folding which results in increased accumulation of unfolded protein [91]. The basic UPR pathway (unfolded protein response) is based on three primary ER-localized transmembrane stress sensors; PERK (double-strand RNA-activated protein kinaselike ER kinase), ATF6 (activating transcription factor 6) and IRE1a (Iinositol-requiring 1 alpha) [92]. GRP78/BiP plays a very important in protein folding by endoplasmic reticulum which

mediates mRNA splicing reaction for the transcription factor X box-binding protein 1. If GRP78/BiP is dissociated from IRE1a it cannot cause protein folding and will lead to UPR. Activated transcription factor 6 is converted to another activated transcription factor 6N by golgi apparatus, then newly formed ATF6N stimulates chaperone and protein folding enzyme expression [93]. Inhibition of ER stress and antioxidants plays an important role in improving renal functions, reduces renal damage by free radicals and ameliorate complications of diabetic nephropathy. Potential antioxidants and ER stress inhibitors against diabetic nephropathy are discussed here.

7.1.

Potential anti-oxidants against diabetic nephropathy

Alpha-Lipoic Acid (ALA) is a potent antioxidant; biosynthesized in both animals and plants. It is having a unique property of getting dissolved in both water and fats [94]. ALA is metabolized to dihydrolipoic acid (DHLA) that plays an important role in free radical scavenging and act as the cofactor for many mitochondrial enzymes. This results in decrease lipid peroxidation and improves nerve conduction and nerve blood flow in diabetic animals. ALA works as an antioxidant by

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inhibiting hexosamine and AGEs pathways [95]. Vitamins A, C, and E are dietary antioxidants which are having a number of biological activities such as inhibition of DNA damage induced by reactive oxygen species or metabolites; immunostimulation and prevention of genetic changes [96–98]. Autocrine C-peptide which is a natural and endogenous antioxidant is shown to work predominantly in the situations of pathophysiological states of hyperglycemia and saturated free fatty acids associated with diabetes [99]. Recent studies have shown that C-peptide can also exert its antioxidant action on b cells by acting through the autocrine mechanism. This autocrine protection supposed to be majorly involved in the treatment of diabetes because as more C-peptide secretion will be there, more will the protection provided by it to b cells; resulting in lesser decay in the functional mass of b cells [100]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are one of the most widely used drug in the treatment of diabetes because of their inhibitory action on dipeptidyl peptidase, an enzyme involved in degradation of GLP-1. This leads to an increase in half-life and elevated concentration of GLP-1 in body [101]. GLP-1 is an endogenous peptide released from L-murine intestinal cells, GLP-1 is involved in stimulation of insulin secretion from pancreatic b-cells and increases the concentration of insulin in the body. These benefits obtained by GLP-1 makes it useful in the treatment of diabetes. Recently, many studies have indicated anti-oxidant potential of DPP-4 inhibitors [102]. Teneligliptin is a DPP-4 inhibitor with antioxidant properties that has been reported to have potential protective action on mild, moderate and severe end-stage renal disease [103]. During in vitro studies using cultured human umbilical vein endothelial cells, teneligliptin was found to promote and improve the antioxidant response and leads to the proliferation of human endothelial cells. It also results in decreased reactive oxygen species (ROS) levels and apoptosis along with the promotion of anti-apoptotic factors [104]. These findings suggest that anti-oxidant therapy may hold a potential for the treatment of diabetic complications including nephropathy. However, more studies are required to pinpoint the exact mechanisms involved and prove the ultimate efficacy of this class of compounds against diabetic nephropathy.

7.2. Inhibitors of endoplasmic reticulum (ER) stress and diabetic nephropathy Unfolded protein response (UPR) lead to ER stress and artificial modulators of UPR could provide protection to the cells [105]. Multiple inhibitors and modulators that are used for inhibition of ER stress are chemical chaperones (sodium 4phenylbutyric acid), anti-oxidative stress compounds (TM2002 and butylatedhydroxyanisole), anti-inflammatory drug (mizoribine) and ER chaperones (ORP150 and GRP78) [106,107]. ER-stress plays a key role in development of diabetic nephropathy and ER-stress inhibitors could be a novel and potent therapeutic approach for the treatment of diabetic nephropathy [108]. Ursodeoxycholic acid or 4-phenylbutyric acid treatment have shown significantly decreased urinary

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albuminuria, markedly decreased expression of CHOP, inhibited production of ROS and attenuated diabetes-induced apoptosis of podocytes or mesangial cell in kidney [109]. Fatty acid-binding protein 4 (FABP4) is a fatty acid transporter protein that play an important role in apoptosis and ER-stress induced diabetes. It could be a potential and novel target for diabetic nephropathy because up-regulation of FABP4 in glomerular mesangial cells causes apoptosis induced by ER-stress in human mesangial cells. FABP4 inhibitors (like BMS309403) needs to be further explored for the treatment of diabetic nephropathy [110]. Another recently found biomarker and drug target for diabetic nephropathy and chronic kidney disease is reticulon 1 (RTN1). ER stress and apoptosis is found to be increased with overexpression of RTN1 in renal cells. Hyperglycemia-induced ER-stress, proteinuria, mesangial expansion, glomerular hypertrophy and renal fibrosis was found to be attenuated with knockdown of RTN1a expression both in vitro and in vivo [111]. Thus, targeting ER stress may prove to be a masterstroke in the treatment of diabetic nephropathy.

8. Novel nephropathy

molecular

targets

in

diabetic

From last few decades conventional targets and mechanisms were utilized for management and treatment of diabetic nephropathy but recent advances in molecular biology techniques and genetic tools have helped in identifying more potent and specific targets [112]. Recently, several enzymes, microRNAs (miRNAs), and epigenetic targets have been explored as potential therapy against diabetic nephropathy [113]. In this review, we have discussed their potential role in the initiation and maintenance of diabetic renal disease so that novel drugs targeting these pathways can be developed.

8.1.

MicroRNAs and diabetic nephropathy

miRNAs are a novel class of non-coding RNAs discovered by Ambros and co-workers, in 1993. This discovery has led to the deep understanding of gene regulation. These are expressed in all human tissues and play an important role in various disease conditions including diabetes [114]. MicroRNAs (miRNAs) are evolving as important regulators of kidney cell gene expression under diabetic conditions. In diabetes, many types of miRNAs are dysregulated in the kidney [115]. Dysregulated miRNAs bind with the 3’UPR of renoprotective genes and decrease their expressions. As a result, dysregulated miRNAs leads to progression of diabetic nephropathy [116]. In Table 1 we have discussed the different miRNA and their role and mechanism in diabetic nephropathy. There are multiple mechanisms by which different microRNA’s may mediate renal injury under diabetic condition. It has been reported that miR-192 and miR-200 leads to the activation of TGF-b1 and fibrosis which may ultimately lead to kidney damage [117]. Moreover, TGF-b also leads to acetylation of chromatin to restore repression of miR-192 in diabetic nephropathy. The induction of miR-192 by TGF-b involves Smad transcription factors which is fol-

Table 1 – A comprehensive list of several miRNAs which are altered (up and down regulated) during diabetic nephropathy. Targets

miR-29 miR-29b miR-29c (Down-regulated)

FBN1, ELN1, MMP2, ITGB1, COL1, COL4 SPRY1

miR-200a/b/c(Down-regulated)

References

 Up-regulation of collagen matrix in mesangial cells via the transforming growth factor-b (TGF-b)/Smad3-dependent  Microalbuminuria, renal fibrosis (TGF-b), and inflammation (NF-jB)  Normal or over expression of these miRNA decrease albuminuria and ECM

TGF-a/Smad3dependent, IFNa, NF-kB (human and db/db mice)

[132,133]

ZEB1/2, TGFb2, b-catenin, FOG

 Long time and high level exposure of TGFb1 and TGF-b2 in Rat proximal-tubular epithelial cells (NRK52E) induced epithelial-to-mesenchymal transition (EMT) and fibrogenesis  Down-regulated expression of miR-200 increase TGF-b1 and TGF-b2 expression  Up-regulation of this miRNA decreases TGFb2, proliferation, COL1, COL4

TGFb1 and b , ECHassociated protein 1/ NFE2-related factor 2 (STZ-induced mice and MMCs)

[134,135]

miR-192(Up-regulated)

dEF1 and Smadinteracting protein 1

 Increase TGF-b expression in mesangial cells  ;COL1a1 and COL1a2, induced TGF-b1

TGF-b1, ZEB1/2, collagen (STZ-induced diabetic C57 mice, db/dbtype II diabetic mice)

[136,137]

miR-195(Up-regulated)

sirtuin1(Sirt1), CyclinE1, BCL2

 B-cell lymphoma 2 (BCL2) protein levels decrease  Increase activation of caspase-3 in podocyte cells

B-cell, Caspase-8, caspase-3 (STZ-induced type 1 mice, podocytes cultured)

[138,139]

miR-124(Up-regulated)

INTEGRINa3b1

 Podocyte adhesion damage under mechanical stress  Increase urinary podocytic nephrin, podocin and albumin excretion

Glomerular basement membrane (GBM), podocyte (Diabetic rats)

[140,141]

 Increased TGF-b1, PAI-1, and FN1

TGF-b1, podocytes, (culture of podocytes and mesangial cells, diabetic mice)

[142,143]

2

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Models and site of action

miR-1207-5p(Up-regulated)

Mechanism involved in diabetic nephropathy

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miRNAs

101

102

miRNAs

Targets

miR-21(Up-regulated)

Akt phosphorylation, mothers against decapentaplegic homolog 7 (SMAD7), TGFb1, tissue inhibitors of metalloproteinase 3 (TIMP3)

miR-377(Up-regulated)

Mechanism involved in diabetic nephropathy

References

 Increase miR-21 regulation of TGF-b1 positively correlates with the severity of fibrosis  Regulation of TIMPs  Increases in Akt phosphorylation

TNF-b1, renal cells (db/db mice, STZ-mice, plasmid and biopsy study of kidney)

[144,145]

PAK1, MnSOD

 Suppression of p21-activated kinase and superoxide dismutase  Enhance FN expression

Kidney (diabetic mice)

[146]

miR-93(Down-regulated)

Vascular endothelial growth factor A (VEGF-A)

 Increase VEGF expression  Normal miR-93 expression prevented expression of VEGF in diabetes

Kidney (Endothelial cells, db/db mice and renal cell culture)

[147]

miR-216a(Up-regulated)

Phosphatase and tensin homolog (PTEN) tumor suppression gene, RNAbinding protein YB-1

 Increased col1a2 expression  Affect processes in cell physiology and biochemistry  Hypertrophy

Mesangial cells, TNF-b1 (renal cells culture and diabetic mice)

[148]

miR-25(Down-regulated)

NOX4

 Increases in NOX4 expression levels

Human mesangial cells (mesangial cells culture and diabetic mice)

[149,150]

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Models and site of action

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Table 1 – (continued)

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Fig. 6 – Epigenetical mechanisms involved in pathogenesis and progression of diabetic nephropathy. Hyperglycemia leads to several post-translational modifications and DNA methylation which ultimately alters chromatin modifications leading to activation of inflammatory and profibrotic genes and decrease in podocin and nephrin expression in renal tissues. TGF-b: Transforming growth factor-b; RAAS: Rennin angiotensin aldosterone system; PKC: Protein kinase C; AGEs: Advanced glycation end products.

lowed by sustained expression promoted by acetylation of the histone H3 [118]. Under hyperglycemic conditions, miR-21 also contributes to renal cell hypertrophy and matrix expansion by affecting phosphatase and tensin homolog (PTEN) tumor suppression gene activity. Overexpression of miR-21 leads to decrease in PTEN levels and increase in Akt phosphorylation and causes pathologic features of diabetic nephropathy [119]. Fiorentino et al. (2013) also reported that, in a mice model of type 1 diabetes, miR-21 were significantly upregulated, which led to downregulation of tissue inhibitors of metalloproteinase 3 (TIMP3) [120]. Recently, TIMP3 deficiency has shown to play a significant role in diabetic nephropathy [121], which indicates that miR-21 is a potential inducer of diabetic nephropathy. Thus, modulation of miRNA may prevent diabetic nephropathy by regulating various biological switches. Induction of kidney protective miRNAs and silencing of inducing miRNAs are some of the ways to restore renal function in patients suffering from diabetic nephropathy [122]. Thus, regulating up-regulation and down-regulation of specific miR-

NAs may be an attractive approach for the treatment of patients suffering from diabetic nephropathy (Table 1).

8.2. Epigenetical nephropathy

mechanisms

involved

in

diabetic

Epigenetics refers to heritable changes and regulation of gene expression that are not related to alteration of DNA sequence. It mainly involves DNA methylation and several types of histone modifications such as acetylation, methylation and phosphorylation [123]. Basically, two types of posttranslational histone modifications (PTMs); histone acetylation and histone methylation, are involved in pathogenesis and progression of diabetic nephropathy (Fig. 6). Progress in the study of histone PTMs in the field of diabetes is still in its infancy. Emerging evidences suggests that histone modifications plays a very important role in diabetes, diabetic complications and metabolic memory. Histone PTMs are reported to be involved in the regulation of insulin expression by pancreatic and duodenal homeobox 1 (Pdx1) in pancreas. Hyperglycemia leads to Pdx1 induced recruit-

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ment of HAT coactivator p300 which could promote chromatin relaxation by increasing histone acetylation and histone methylation to enhance insulin transcription. Moreover, Pdx1 may also inhibit insulin expression when glucose levels were low by recruiting HDACs [124,125]. Moreover, HDACs are also reported to be involved in acetylation of several transcription factors involved in adipocyte differentiation, suggesting their potential role in metabolic disorders [126]. Histone PTMs also reported to be involved in induction of gene expression in monocytes and macrophages, which plays key role in macrophage infiltration and inflammation [127]. Hyperglycemia-induced inflammatory gene expression is reported to be associated with increased promoter H3/ H4KAc and enhanced recruitment of HATs which leads to increase in proinflammatory transcription factor NF-jB in monocytes [128]. Other post-translational histone modification may also be involved in diabetic nephropathy such as decrease in H2B ubiquitination and increase in H2A ubiquitination in renal mesangial, and glomerular cells [129]. Gao et al. (2013) found that H2A ubiquitination is significantly increased in glomerular mesangial cells of high glucose treated group as compared to control and drug treated group. Contrary to this H2B ubiquitination was found to be significantly decreased with an increasing concentration of glucose [130]. Diabetic condition causes several modifications in renal cells by altering gene regulation which in turn causes inflammation and activation of profibrotic genes, responsible for induction of inflammation and hypertrophy of kidney [131]. However, more research is required to further explore the key epigenetical mechanism and make them clinically translatable in patients suffering from diabetic nephropathy.

9.

Conclusion

Diabetic nephropathy is one of the most prevalent and lifethreatening complications of diabetes. This review has discussed the numerous factors and pathophysiological mechanisms involved in the progression of diabetic nephropathy, targets and therapeutic approaches to reduce renal injury and improve kidney function. We have also provided new insights into the inhibition of diabetic nephropathy using targets known for a long time. To develop new and safe line of therapies, novel biomarkers for treatment efficacy needs to be established along with studying the long term effect of drugs on renal structural features in clinical studies. We have also put light on new epigenetical and molecular targets being investigated against diabetic nephropathy. In future therapeutic approaches might be based on epigenetics and miRNAs and targets of specific signaling pathway for the treatment of diabetic nephropathy. There are bright prospects that combination therapies with epigenetic drugs and miRNAs modulators may complement the current treatment approach of diabetic nephropathy. Further research in the existing and novel molecular targets would be helpful in the identification and validation of new biomarkers and drug targets for early detection and treatment of diabetic nephropathy.

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Conflict of interest No conflicts of interest exist.

Acknowledgement This work is supported by Department of Pharmaceuticals, Ministry of Chemical and Fertilizer, Government of India and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, Gujarat, India. Authors also want to express their thanks to Director, NIPER Ahmedabad for providing necessary facilities and infrastructure.

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