Osmolytes resist against harsh osmolarity: Something old something new

Biochimie 158 (2019) 156e164

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Biochimie journal homepage: www.elsevier.com/locate/biochi

Review

Osmolytes resist against harsh osmolarity: Something old something new Seyed Mahdi Hosseiniyan Khatibi a, Fatemeh Zununi Vahed b, Simin Sharifi c, Mohammadreza Ardalan b, Mohammadali Mohajel Shoja d, Sepideh Zununi Vahed b, * a

International Rice Research Institute (IRRI), Los Banos, Philippines Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 4 September 2018 Accepted 3 January 2019 Available online 7 January 2019

From the halophilic bacteria to human, cells have to survive under the stresses of harsh environments. Hyperosmotic stress is a process that triggers cell shrinkage, oxidative stress, DNA damage, and apoptosis and it potentially contributes to a number of human diseases. Remarkably, by high salts and organic solutes concentrations, a variety of organisms struggle with these conditions. Different strategies have been developed for cellular osmotic adaptations among which organic osmolyte synthesis/accumulation is a conserved once. Osmolytes are naturally occurring solutes used by cells of several halophilic (micro) organisms to preserve cell volume and function. In this review, the osmolytes diversity and their protective roles in harsh hyperosmolar environments from bacteria to human cells are highlighted. Moreover, it provides a close look at mammalian kidney osmoregulation at a molecular level. This review provides a concise view on the recent developments and advancements on the applications of osmolytes. Identification of disease-related osmolytes and their targeted-delivery may be used as a therapeutic measurement for treatment of the pathological conditions and the inherited diseases related to protein misfolding and aggregation. The molecular and cellular aspects of cell adaptation against harsh environmental osmolarity will benefit the development of effective drugs for many diseases. © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Keywords: Compatible solutes Osmoadaptation TonEBP/NFAT5 Protein aggregation Renal cells

Contents 1. 2.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Osmolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 2.1. Varieties in organic osmolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 2.2. Biological functions of osmolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 Osmoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3.1. Osmoregulation signaling pathways in nature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 3.2. Osmoadaptation of mammalian cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 3.2.1. TonEBP/NFAT5 transcription factor regulates the concentrations of osmolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 3.2.2. Osmolyte synthesis/accumulation in response to the TonEBP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 The role of hyperosmotic stress in diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Applications of osmolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 5.1. Therapeutic potential of the osmolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

* Corresponding author. E-mail addresses: [email protected], (S. Zununi Vahed).

[email protected]

https://doi.org/10.1016/j.biochi.2019.01.002 0300-9084/© 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

S.M. Hosseiniyan Khatibi et al. / Biochimie 158 (2019) 156e164

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5.2. The need for understanding the molecular mechanism for osmolyte-induced protein stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 Financial Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

1. Introduction From the halophilic bacteria to humans, cells have to survive under the stresses of harsh environments. Osmotic stress creates too much survival struggle and demands appropriate cellular responses. These responses are accomplished by different alterations at the molecular level that cause cellular adaptation. Under the hyperosmotic conditions, cells rapidly lose their water due to osmosis, leading to a rapid cell shrinkage that increases ionic strength [1,2]. Moreover, concentrations of cellular components like macromolecules and inorganic ions are increased and the reorganization of the cytoskeleton takes place. These events disturb proteins function because of macromolecular crowding that can influence reactive oxygen specious (ROS) production, DNA damage, cytoskeletal rearrangement, inhibition of transcription and translation, mitochondrial depolarization [1], and different activity of kinases and other enzymes involved in osmotic stress signaling (Fig. 1). Not only in sever hypersalinity, but also during less prominent changes in extracellular fluid osmolality, mammalian cell death may happen through apoptosis and necrosis [3]. For the survival and cellular adaptation under osmotic pressure, different strategies have been developed with an aim to turn back the cell volume to normal size and preserve cellular functions and homeostasis. Kidney is an essential mammalian organ for osmotic regulation. Renal medulla provides a high osmolality that is needed for water reabsorption to preserve the body fluid. Kidney medullary cells by themselves should tolerate the exposed high concentration of salt and urea and, in part, remain functional [2]. Lessons from the halophilic organisms’ survival under the extreme stress in nature and understanding the strategies by which the kidney cells survive have led to the discovery of organic protective adaptation molecules called osmolytes. These solutes are low-molecular-weight, relatively non-toxic, and water-soluble organic compounds [4] that can be employed by a variety of

organisms as an adaptation mechanism to extreme conditions. Organic osmolytes including amino acids, polyols, sugars, and their derivatives, except urea, are also named compatible solutes. Organic osmolytes preserve cellular osmotic balance, cell volume, and redox states. The evolutionary importance of the osmolytes is their compatibility with the cellular metabolism, hemostatic mechanisms, and macromolecular structures that are mediated through charge-mediated surface interactions and their accumulation without disturbing the orchestration and organization of the cells [5e7]. The biological function of the osmolytes within the renal medullary cells is to guard the intracellular biomolecules against the disturbing effects of highly concentrated urea and salt ambient. Therefore, osmolytes can be considered as osmo-protectant and bio-protectant molecules in the organisms. Mammalian brain, liver, and heart cells also accumulate some osmolytes. In this review, we aim to highlight the osmolytes diversity and their protective roles in the harsh hyperosmolar environment from the bacteria in nature to human cells. Moreover, this article clarifies the application of osmolytes as possible drugs in the treatment of numerous diseases.

2. Osmolytes Hypo- and hyperosmotic shocks can be blocked by osmoadaptation mechanisms by which biomolecules can be defended from osmotic changes. For maintaining cell volume, organic osmolytes are accumulated. An enormous number of organisms have evolved by regulating their cellular levels of osmolytes to make an adjusted response under the hyperosmotic condition and they adapt to perturbations with some structural changes in their cellular proteins [8].

Fig. 1. Cellular responses to hyperosmolarity. Elevated fluid osmolarity affects cells negatively through rapid water efflux and subsequent cell shrinkage. High concentration of NaCl causes NaCl-induced DNA damage resulting in activation of repair mechanisms or induction of apoptosis. Cells respond to the extracellular hyperosmolarity in a time course manner (within hours) by different adaptation processes at molecular and cellular levels.

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2.1. Varieties in organic osmolytes A large number of small molecules have been found to work as organic osmolytes. These solutes are divided into 4 major groups: carbohydrates comprising sugars (trehalose), polyols (e.g., sorbitol, inositols, glycerol, etc.), and their derivatives (o-methyl-inositol); amino acids (glycine, proline, taurine, etc.) and their derivatives (e.g. ectoine); methylsulfonium solutes like dimethylsulfonopropionate and methylamines (glycine betaine and N- trimethylamine oxide); and urea [9]. Except for the urea that just a small variety of animals use, other groups of osmolytes are commonly used by most of the cells. For example, taurine is very common among marine animals and less common in some mammalian organs, while glycine betaine can be found more widely among different living organisms. In algae, plants, fungi, and deep-sea invertebrates, carbohydrate is the main osmolytes. Mammalian kidney cells, particularly in the hyperosmotic deep medulla, employ glycine, betaine, taurine, polyols, myo-inositol, sorbitol, and methylamines glycerophosphorylcholine (GPC) to resist against the high concentrated interstitial urea and sodium. Many organisms use a combination of different osmolytes groups. Different organic solutions used by halotolerant and halophilic organisms are listed in Table 1. 2.2. Biological functions of osmolytes It is obvious that the accumulation of specific osmolytes regulates many biological processes such as protein folding, proteineprotein interactions, and can even inhibit the aggregation of proteins and reverse their misfolding [10,11]. Osmolytes stabilize the structure of proteins thermodynamically and protect the function of intracellular enzymes; therefore, function as chaperones [12]. A recent study of Aasif Dar et al. confirms that osmolytes in the kidney have positive effects on the folding, stability, and function of kidney proteins exposed to urea constantly [13]. It is reported that non-methylamine osmolytes including sorbitol and myo-inositol can neutralize the harmful effects of urea on the structure and stability of mammalian kidney proteins [14]. Besides the structural stabilization, osmolytes present antioxidation properties and are involved in several other biological processes comprising immunological adaptations [15], Hostpathogen interaction, cell volume regulation, and regulating cell metabolism and signaling pathways [10,16,17]. Recently, there is increasing attention toward the osmolyte-induced stability and action of osmolyte compatibility [8]. Additionally, osmolytes

protect proteins against temperature-induced denaturation [18]. Intracellular osmolytes are also essential for the inhibition of apoptosis in kidney medullary interstitial cells. Osmolytes inhibit the depolarization of mitochondria and reduce mitochondrial membrane permeability for efflux of proapoptotic factors. It is also reported that osmolytes can lower inflammation. The biological roles of osmolytes on proteins are reviewed comprehensively in the literature [10,11,19]. It is noticeable that not all the time osmolytes have protective roles, but during hyperosmotic environment, the cell starts to synthesize defensive organic osmolytes to preserve the ideal osmotic pressure and cell volume. When the defensive osmolyte response is diminished, cell death occurs in kidney cells [20] and hyperosmolarity induces necrosis or apoptosis in these cells [19]. The accessibility of the environmental osmolytes and substrates, a magnitude of osmotic pressure, and various buffering potential are the effective factors in the selection of osmolytes by different cells and organisms. 3. Osmoregulation Despite alteration in environmental factors, the organism's fluid homeostasis is severely controlled and the intracellular osmotic pressure is generated to prevent the water loss. Under different physiological and pathological circumstances, cells are also exposed to osmotic stress. Osmoregulation, a significant role of osmolytes, retains the proper fluid content (water and electrolyte concentration) within the cell of the (micro) organism. Different (micro) organisms apply diverse strategies to preserve the right cellular concentration of water and solutes, some of which are described in the following sections. 3.1. Osmoregulation signaling pathways in nature In nature, a wide range of halophilic organisms are adapted to survive in harsh salty conditions [21]. These organisms are hassled by two factors; the high concentration of inorganic ion and the low water potential [22]. Different strategies have been established for cellular osmotic adaptations most of which are conserved from bacteria to human [23]. In the processes of osmoadaptation, a cell monitors the situation and then regulates osmotic pressure, cell shape, and water content [23]. Halophilic micro-organisms (bacteria and archaea) have developed salt-in and salt-out mechanisms to counterbalance the osmotic pressure change [4,24]. The salt-in strategy is a selective Kþ ions influx strategy. For proper cell function, a complete cell

Table 1 Different organic solutes used for osmotic balance in halotolerant and halophilic organisms. Organisms

Organic solutes

References

Bacteria &Archaea

Neutral or zwitterionic solutes betaine, Ectoine, hydroxyectoine, Ng-acetyldiaminobutyrate, Ne-acetyl-b-lysine, and b-glutamine Noncharged solutes

[4,10,24,82,83]

 Carbohydrates: a-glucosylglycerol, a-mannosylglyceramide, Trehalose, Sucrose  Uncharged Amino Acids and Peptides: N-a-carbamoyl-L-glutamine 1-amide and N-acetylglutaminylglutamine amide Organic anions  anionic solutes (carboxylates): L-a-glutamate, В-glutamate, hydroxybutyrate, poly-b-hydroxybutyrate, a-glucosylglycerate, amannosylglycerate  Anionic solutes (phosphate, sulfate):Sulfotrehalose, cyclic-2,3 diphosphoglycerate, a-diglycerol phosphate, di-myo-inositol-1,1‘-phosphate, mannosyl-DIP Yeast & Fungi Glycerol, trehalose,glycerophosphocholine Polyols: erythritol, ribitol, arabinitol, xylitol, sorbitol, mannitol, and galacticol. Plants Proline, valine, isoleucine, ectoine, aspartic acid, betaine, glucose, fructose, sucrose, fructans, mannitol, pinitol, and inositol Marine Animals Deep sea invertebrates: scyllo-inositol, b-alanine, betaine, hypotaurine, and N-methyltaurine Cartilaginous fish: urea and methylamines (trimethylamine N-oxide, betaine, sarcosine) Mammalian Polyols: sorbitol and myo-inositol, trimethylamines betaine, glycerophosphocholine (GPC), and free amino acids like taurine

[26,27] [28] [19] [40]

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structural components and enzymes adaptations are needed to resist high salinity [21,25]. The most commonly used salt-out strategy (osmolytes) is applied by most of halophilic bacteria and eukaryotes. Saccharomyces cerevisiae that is a yeast model system for osmoadaptation study and exclusively employs glycerol and less commonly exercises trehalose and glycerol phosphocholines. Other yeasts and fungi produce or accumulate diverse polyols including galacticol, ribitol, sorbitol, mannitol, erythritol, xylitol, and arabinitol [26,27]. Plants cells subjected to hyperosmotic stress accumulate organic osmolytes including; sugars (glucose, fructans, fructose, mannitol, sucrose, inositol), amino acids (betaine, proline, isoleucine, aspartic acid, valine, ectoine), and pinitol in their cytoplasm [28]. Sharks, rays, and skates that belong to Elasmobranchs subclass of cartilaginous fish have an osmoregulatory system that accumulates urea and methylamines in their tissues. Methylamine decreases the denaturing effects of urea [5]. 3.2. Osmoadaptation of mammalian cells Human blood osmolarity is normally kept within a constant range (285e295 mOsm/kg) and complex regulatory mechanisms including antidiuretic hormone, renineangiotensinealdosterone systems, and a combination of thirst and urinary concentration mechanisms are tuned toward this direction [6,19]. Yet, the normal renal function needs an interstitial osmotic gradient (4 times more than plasma osmolarity) in the kidney medulla [19]. The early event that starts osmotic response is not completely understood in mammalian cells. The capability of cells to adjust to a hyperosmotic stress includes early reactions that ions transport through the cell membranes. The late responses are mediated by osmolytes. In renal medullary tissues, organic osmolytes have developed as protective agents under osmotic stress and their cellular concentrations are regulated by the rate of their synthesis and transportations. The elevated synthesis of molecular chaperones (e.g., heat shock proteins) is another adaptive procedure for cell survival [29]. Mammalian's medullary cells comprise the highest levels of five organic osmolytes including sorbitol, betaine, inositol, taurine, and GPC, among which betaine and myo-inositol are the most important. Three fundamental mechanisms of osmo-adaptation include (1) a higher cellular uptake of betaine, myo-inositol and amino acids from the extracellular space, (2) intracellular production of sorbitol and GPC, and (3) decreased degradation of intracellular GPC. Besides osmotic balancing, betaine and GPC preserve medullary kidney cells from the hostile effects of high concentrations of urea. 3.2.1. TonEBP/NFAT5 transcription factor regulates the concentrations of osmolytes Following the exposure to osmotic stress, cells should develop several adaptive genetic mechanisms to allow their cell survival, otherwise , stress leads to oxidative stress, disruption of homeostatic processes, protein carbonylation, mitochondrial depolarization, and impairment of hemostatic process that hamper the cell survival [6]. Extracellular fluid hyperosmolarity is sensed by changes in the cytoskeleton and/or yet undiscovered osmosensors. In response to osmotic stress in renal cells and lymphocytes but no other stimuli, a signaling cascade starts the activation of mitogenactivated protein kinase (MAPK or MAP kinase) pathway that is regulated by the guanine nucleotide exchange factor Brx [30]. Brx responses to the signal of hyperosmolarity through forming a complex with small p38 MAPK, JIP4, and G-proteins and its upstream kinases to trigger the transcription of genes involved in

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osmotic stress-responsive [31]. The MAP kinase pathway(s) activation leads to the activation of ion transporters for the entrance of sodium and chloride ions to restore cell volume through a passive influx of water. However, a high concentration of NaCl can induce DNA double-strand breaks, cell-cycle arrest, and ultimately apoptosis [32]. To overcome these adverse effects, cells have evolved a series of intracellular phenomena often mediated by the transcriptional activator called tonicity-responsive enhancer binding protein (TonEBP) also known as nuclear factor of activated Tcells 5 (NFAT5) [33,34]. The accumulation of TonEBP/NFAT5 in nucleus starts within 30 minutes following an increase in tonicity [1]. Data support that Brx plays a significant role in the regulation of the TonEBP in a variety of cell types [30]. TonEBP is a crucial factor in kidney health. It is an essential regulator of cellular protection against damaging hyperosmolality. Moreover, it is involved in the development and function of the kidney medulla and also urine concentration. High concentration of NaCl raises TonEBP transcriptional activity via several signaling pathways [35]. TonEBP stimulates the expression of various transporters such as the betaine-GABA-transporter (BGT-1), the sodiummyo-inositol transporter (SMIT), and the taurine transporter (TauT) involved in the accumulation of organic osmolytes. Moreover, TonEBP promotes aldose reductase (AR) and neuropathy target esterase (NTE) enzymes involved in the synthesis of sorbitol and GPC, respectively [36] (Fig. 2). It is also reported that decreased levels of TonEBP in the settings of hypertonic stress lead to renal papillary necrosis [37] in rat tubule cells. Furthermore, TonEBP regulation of its downstream gene expressions like AR, TauT, BGT-1, and SMIT is a vital mechanism to guard kidney cells against the corticomedullary gradient that is necessary to conserve water and concentrate urine in desert rodents [38]. 3.2.2. Osmolyte synthesis/accumulation in response to the TonEBP In response to the TonEBP, sorbitol is synthesized and catalyzed from AR in renal medullary cells; in the inner medullary collecting ducts and the ascending thin limb of Henle's loop [1]. The accumulation of sorbitol requires the elevation of AR mRNA and protein levels and the attenuation of sorbitol dehydrogenase (SDH) expression that oxidizes sorbitol to fructose. Under the hyperosmotic conditions, a zinc-finger protein ZAC1 is upregulated and led to downregulation of SDH, allowing the sorbitol accumulation [39]. Since the entire concentration of osmolytes in the cell is important, the elevated level of glycine betaine reduces the activity of AR enzyme in the cells. The amount of betaine also increases by hypertonicity [1,40]. In liver and kidney, betaine is synthesized via choline. Despite sorbitol, hypertonicity has no effect on the rate of betaine synthesis but it increases the transcription and translation of BGT1. In other words, tonicity can regulate betaine transportation by influencing BGT1 transcription rather than betaine synthesis. Moreover, plasma membrane insertion of BGT-1 in renal cells is elevated, results in increased levels of GABA and betaine transport [41]. Freely, betaine is filtered and actively reabsorbed by glomeruli and kidney tubules, respectively [40]. For each transported betaine, BGTl couples 3 Naþ and 1 (2) Cl ions [36]. BGT1 is regulated by hypertonicity and TonEBP and also its localization into apical and basolateral plasma membranes in tubular cells since, under normotonic conditions, the BGT1 resides fundamentally in the cytoplasm. Moreover, increased levels of BGT-1 under a hyperosmotic shock need the posttranslation regulation of the protein mediated by glycosylation of the transported with N-glycans that is dependent on intracellular ATP and calcium [41,42]. A myriad amount of betaine (accounts for 25% of the total content of osmolytes) and its high proteinstabilizing features make it an essential osmolyte in kidney medullary cells [40]. Moreover, betaine prevents the apoptosis of cell

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Fig. 2. Molecular mechanisms in response to hyperosmolarity. The ability of cells to adapt to hyperosmotic stress involves early responses in which ions move across cell membranes and late responses characterized by increased synthesis of either membrane transporter essential for the uptake of organic osmolytes or of enzymes involved in their synthesis. In renal medullary cells, expression of TonEBP/NFAT5 is stimulated by interstitial hypertonicity and its phosphorylation occurs via several signaling pathways. An active form of TonEBP enters the nucleus and stimulates the expression of various transporters such as the SMIT, BGT-1, and TauT involved in the accumulation of organic osmolytes. TonEBP also promotes AR enzyme involved in the synthesis of sorbitol. Moreover, TonEBP-mediated expression of heat shock proteins provides protein stability against misfolding to allow cell survival. AR: aldose reductase, SMIT: sodium-myo-inositol transporter, BGT-1: betaine-GABA-transporter, TauT: taurine, ROS: reactive oxygen specious.

exposed to hypertonicity by prohibiting the activation of caspase 3 and the upregulation of the translation of antiapoptotic genes including XIAP (X-linked inhibitor of apoptosis protein) and Bcl-2 (B-cell CLL/lymphoma 2) [43]. Hypertonicity also increases intracellular inositol [1]. An elevated level of inositol is seen as a result of its transportation rather than its synthesis by renal cells. When the amount of SMITs increases by hypertonicity, it leads to cellular accumulation of inositol. Hypertonicity promotes transcription and translation of the SMIT gene. SMIT couples the inositol and sodium transportation. Myo-inositol is also the precursor of phosphoinositides lipids. Dai et al. found a linkage between extracellular osmotic changes and the electrical properties of excitable cells. They found that cellular accumulation of myo-inositol can elevate phosphoinositide levels and alter the activities of phosphoinositide-dependent ion channels [44]. TauT is the osmoregulated taurine transporter that is depended on sodium- and chloride and its mRNA and protein levels increase by hypertonicity. Taurine increases with hypertonicity as it is taken up from extracellular fluid [1]. GPC is a special organic osmolyte in renal medullary that aggregates in response to hypertonicity along with high urea [1]. GCP synthesize from phosphatidylcholine by NTE. The GPC degradation decreases and its synthesis increases with the high amount of NaCl. It's necessary to know that in renal medullary cells high levels of urea not only increases the GPC but also it decreases the GPC degradation; however, urea reduces betaine levels [19]. The difference is significant, but its evolutionary basis remains conjectural [19,45]. The synthesis of protectant osmolyte requires a lot of energy and the applied osmolyte in nature needs to be as effective as possible [46]. A lower metabolic cost of GPC accumulation would be the preference for GPC in response

to high urea [47]. The promoters of the UT-A (urea transporter) and AQP2 (water channels) genes are stimulated by TonEBP and all of them are highly expressed in the collecting duct. Induction of AQP2 and UTA stimulates the permeability of the collecting duct water and secretion of urea into the medullary interstitium and leads to the urinary concentration [48]. The study of Hinze et al. outlines a novel function for the collecting duct epithelium in renal osmoregulation. Epithelial cells produce grainyhead-like 2 (GRHL2), a transcription factor, that causes the expression of tight paracellular barrier components. This event inhibits the leakage of interstitial osmolytes into urine and leads to body water homeostasis. In the interstitium of the renal medulla, high concentrations of osmolytes run the driving force for transcellular water reabsorption in the collecting duct [49]. The prostein, known also as solute carrier family 45 a3 member (SLC45A3), is another osmolyte transporter and a proton-coupled sucrose symporter in the mammalian kidney. Vitavska et al. indicated that under hyperosmotic stress, SLC45A3 upregulates and transports the sucrose (a disaccharide) and possibly glucose and fructose (monosaccharides) from urine into renal epithelial cells. They proposed that these sugars may function as novel compatible osmolytes in urine [50]. By the accumulation of osmolytes, renal cells survive and look healthy under hyperosmolarity; however, they experience DNA strand breaks and also proteins and DNA bases oxidation [1]. Studies have found that osmotic stress response is not absolutely restricted to renal cells and it can impact a variety of cell type [51]. In other organs and isotonic tissues, TonEBP involves in different physiological and pathophysiological procedures [48]. When these cells are exposed to hyperosmotic conditions, they

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accumulate organic osmolytes. For example, amino acids, choline, creatine, inositol, and taurine [52] along with betaine, inositol, and taurine [53] are respectively accumulated in the brain and liver. 4. The role of hyperosmotic stress in diseases Hyperosmotic stress triggers protein and DNA damage, cell cycle arrest, and cytoskeleton rearrangement. Furthermore, osmostres changes a variety of cell function by regulating the genes transcription, translation, post-translation, and protein activity. Under non-pathogenic conditions, some other cells and tissues including liver, intervertebral discs, the cornea, lymphoid tissue, gastrointestinal tract, and joints are also exposed to hyperosmotic fluids. A number of factors can influence the osmotic pressure and cause micro-environmental osmotic imbalances; for instance, elevated concentrations of urea, high sodium and glucose levels in the blood (hypernatremia and hyperglycemia, respectively), amino acid starvation, and oxidative stress. In this respect, many cell types and tissues are exposed to hyperosmotic stress leading to the initiation and progression of diseases such as inflammatory statues (cancers, asthma, and cystic fibrosis), dry eye, liver and cardiovascular diseases [6,54,55]. Likewise, obesity [56], diabetes and reduced glucose tolerance [57,58], diabetic retinopathy [58], and aging [55] are associated with elevated plasma osmolarity. Under these circumstances, inflammation responses may occur. Pathologic situations that are associated with extracellular hyperosmolarity can change the white cell's functions via activation of a signaling pathway mediated by Brx/NFAT5 [31]. Damaging agents and cytokines along with osmotic stress lead to an inflammation that accumulates the macrophages and lymphocytes in an inflammation site. The cellular signaling system mediated by Brx/ NFAT5 induces the expression of cytokines in order to modify the inflammatory responses, whereas it stimulates the hyperosmoticresponsive genes to guard immune cells against the local hyperosmolar environment [31]. Moreover, hypertonic situations severely induce cell cycle arrest in the retinal pigmented epithelial cell by decreasing the expression of cyclin D1 and cyclin B1 [51]. It is believed that hyperosmotic stress can also enhance cellular susceptibility to the liver and renal tubular fibrosis [59]. In mammalian kidney, the mechanism of urine concentrating needs an increased renal medullary urea and NaCl concentration, low medullary circulation meanwhile creates a hypoxic condition. Under this stressful condition, reactive oxygen species (ROS) are elevated. Since the osmolyte synthesis enzymes are susceptible to ROS damage [60], reduction in the activity of these enzymes and osmolyte concentration are connected to kidney injury, resulting in the generation of ROS-related kidney diseases (e.g., tubulointerstitial nephritis, proteinuria, glomerulonephritis, and hypertension) [60]. Gil et al. (2018) demonstrated that increased urine levels of kidney osmolytes (e.g., betaine and myo-inositol), due to their transporter downregulation, are connected with chronic kidney disease (CKD) severity and progression rate. Therefore, these osmolytes can present clinical diagnostic and prognostic information on CKD outcomes [40]. Moreover, a significant alteration in renal metabolic and osmolyte profile including urea, pinitol, and taurine is detected in an animal model of sepsis. Definitely, by understanding the fundamental mechanisms, future research can prevent acute kidney injury in the setting of sepsis through the development of attentive cellular targets [61]. 5. Applications of osmolytes

in

Now, it is obvious that osmolytes have a variety of applications agriculture, meat industries, microbiology, cosmetics,

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biotechnology [62], molecular biology, and pharmacology (reviewed in Ref. [11]). Moreover, they would be useful in the prevention and/or treatment of different human diseases (Table 2). The identification of the dysregulated osmolytes under specific diseases can be valuable for the development of diagnostic strategy and selective use of osmolytes against a disease. Additionally, the development of approaches for the tissue-specific delivery of osmolytes would sound great [10]. 5.1. Therapeutic potential of the osmolytes In the kidney, methylamines have protective effects on macromolecules against the urea-induced stress. So, employing definite methylamine osmolytes may be effective in the treatment of uremic patients. Moreover, it is reported that methylamines downregulation can be a cause for the development of polycystic kidney disease. Therefore, changing the osmolyte content may be an effective therapeutic agent for the disease. In addition to their involvement in biological processes, osmolytes can be used as a therapeutic mechanism in disease condition to protect misfolded/aggregation-prone proteins [10]. Generally, the mechanism of protein folding that relates to osmolytes can be used as a remedial target for disease. Self-association, misfolding, and fibrillation of amyloidogenic peptides and proteins are the main hallmarks of several neurodegenerative diseases. Wu et al. studied the role of crowding environments in the regulation of Tau fibrillation to clarify the etiology and the molecular mechanisms of Alzheimer's disease. They observed that native cellular osmolytes (sucrose) can prevent Tau fibrillation and have a therapeutic potential to treat the disease [63]. Likewise, in Huntington's disease model, trehalose can be used as a preventive agent [64]. Certainly, understanding the importance of osmolytes on protein folding in pathological conditions can be found as novel management and preventive tool in the diseases that are related to protein misfolding in the near future. Some of the therapeutic potentials of the osmolytes are listed in Table 2. 5.2. The need for understanding the molecular mechanism for osmolyte-induced protein stability The application of osmolytes as protein protectant has gained attention because of their stability against different types of stresses and their economic point of view that present an important industrial impact. It should be considered that the activity and thermodynamical stability of proteins are very important issues that may limit their medical and industrial applications. Likewise, the efficiency and maximum yield of enzyme-catalyzed reactions can be restricted by the stability/activity of enzymes and their thermodynamic equilibrium [65]. Therefore, understanding the functions of organic osmolytes and their molecular interactions at counteracting stressful conditions and in disease requires detailed knowledge of their modes of action [46]. In order to optimize the use of osmolytes in protein stabilization, the knowledge of their molecular interactions [46], their role in reaction kinetics [66], and reaction equilibria [65] of enzyme-catalyzed reactions would be important issues. Moreover, a comprehensive data analysis is needed for osmolytes to understand their molecular adaptation to different natural environments. Diverse views on the underlining mechanisms of proteinstabilizing effects of osmolytes in solution exist in the literature. Both effects of the osmolyte on the water structure and direct interactions with protein are essential for the improvement of the protein stability. However, the stability of proteins in the presence of osmolytes is a crosstalk between protein characteristic and osmolyte concentration and its chemical nature that confuse the

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Table 2 Pharmaceutical and clinical applications of osmolytes. Osmolyte

Function

Mannitol, sucrose, and trehalose

Stability of protein

Glycerol, sorbitol, TMAO, proline, and glycine Glycine betaine

Betaine

Monosaccharides (glucose), disaccharides (sucrose), and sugar alcohols (mannitol, glycerol) Ectoine

Trehalose

Protectant of biomolecules

A bioprotectant

Neuroprotection Induces and/or inhibits autophagy

Taurine

Sorbitol and trehalose

Osmolytes

Results

Osmolytes enhance the stability and kinetic activity of the Tenecteplase: a therapeutic protein and triplecombination mutant of human t-PA Production of protein Osmolyte induced the expression, yield, and solubility of (hDHFR) the functional hDHFR protein. Osmolytes lack the ability to cross the blood brain barrier Plays a role in protein synthesis by regulating the Regulates cell enzymes activity (either via changing their expression metabolism and modulates the expression levels or their phosphorylation status). of genes Neuroprotection Betaine implicates in the modulation of hippocampal neurophysiology and neuroprotection under osmotic stress Cryoprotectants

Induces -autophagy -cell survival

Protect the protein (myoglobin) conformation and structure Regulating the immune system

Application

Ref.

Thrombolytic therapy

[67]

Treatment of several neurodegenerative diseases

[69]

Metabolic disorders related to the metabolism of carbohydrate and lipid can be decreased by GB

[17]

Nervous system

[70]

Mesenchymal stromal cell survival

[71]

-Applied as a scavenger -Skin - Protection of DNA against ionizing radiation - Protection of cells and enzymes against drying, protection -anti-inflammatory treatment freezing, salinity, and heating -Has inhibitory effects in neurodegenerative diseases - A protectant and chemical chaperone - Stabilization of vaccines and - Inhibits the oxidation of certain fatty acids liposomes - The hypothermic storage of human organs - The treatment of dry eye syndrome and dry skin in humans Directly acts on neurons and induce autophagy, thereby A novel therapy for neurodegenerative promoting the clearance of protein aggregates. diseases Stimulation of autophagy by trehalose hampers ALS, and A therapy for neurodegenerative diseases, cancer, aging, metabolic FTD development. Inhibition of autophagy in brain ischemia and diabetic disorders, and infectious diseases. nephropathy. Reduces retinal degeneration, neuroinflammation A treatment for LSDs - By reducing cell apoptosis level protects retinal Ophthalmology ganglion cells and lens epithelial cells against UVB - May treat cataract osmolytes can protect the protein structure from the Cancer therapy reactive species generated by gamma rays and DBD plasma. -

Immune cells proliferation Immunoglobulin assembly and folding, Regulation of immune cells function, Ag-Ab interaction, antigen presentation, inflammatory response

[72,73]

[74]

[75] [76]

[77] [78 e80] [81]

Osmolytes and their transporters might [15] be used as potential drug and drug targets respectively.

t-PA: tissue plasminogen activator, hDHFR: human Dihydrofolate reductase, DBD: dielectric barrier discharge, LSDs: lysosomal storage disorders.

prediction of protein stability [67,68]. Furthermore, several forces are involved in the interaction of proteins and osmolyte. It should be considered that osmolytes interact with diverse protein molecules in a different way and based on the nature of the interacting forces, stabilization or destabilization of the macromolecule could be the final result [10]. Stabilizing behavior of osmolytes towards protein stability has been confirmed by vast literature. In spite of the enormous applications of organic osmolytes in protein science, their interaction with the protein remains a matter of consideration [45]. 6. Conclusion The capability of osmoadaptation is crucial for all organisms especially those living in hypersaline environments. Although mammalian cells and tissues that are exposed to hypertonic stress have developed counteractive mechanisms, acute or chronic hypertonicity can promote cell apoptosis and tissue damage. Indeed, a

comprehensive understanding of the molecular and cytoprotective mechanisms involved in the adaptation of halophilic (micro) organisms would increase our understanding and ability to prevent and manage the treatment of diseases arise from high osmotic pressure. Data support the idea that osmolytes will have enormous applications in the treatment of human diseases. Since the influx of osmolytes into the cell is a general response to hyperosmolarity, therapeutic targeting of associated pathways and induction of involved genes is a promising task before the occurrence of NaClinduced DNA damage. The identification of disease-related osmolytes and their targeted-delivery may be used as a therapeutic measurement. Osmolyte therapy can be helpful in drug design for the inherited diseases related to protein misfolding and aggregation. Conflicts of interest The authors declare no conflict of interests.

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