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Understanding Serotonin 5-HT2A Receptors-regulated cellular and molecular Mechanisms of Chronic Kidney Diseases

Renal Replacement Therapy volume 6, Article number: 25 (2020) Cite this article

Abstract

Chronic kidney diseases (CKD) are an economic burden and occur worldwide in all age groups, and the advancement of kidney disease at some point leads to deregulate or influence the function of other body organs and to find a specific target to halt the disease progression which is a tedious challenge. Regardless of the underlying mechanisms, it is essential to consider and evaluate the involvement and association of individual endogenous mediators and environmental factors in the progression of CKD to accumulate the required knowledge. More than a dozen pathways leading to relentless progression of CKD have been identified so far, but the association of serotonin 5-HT2A receptor with progressive renal injury is still under process.

Scientific reports demonstrated that the 5-HT2A receptor plays a significant role in renal metabolism, glomerular function, and renal vascular tone. So a better understanding of the evolving role of serotonin 5-HT2A-mediated pathophysiological mechanisms of CKD may be a helpful tool to identify new therapeutic targets. In this review, we will discuss recent interventions, pharmacological target, and the possible implication of serotonin 5-HT2A receptors with associated mechanistic trails leading to CKD.

Introduction

Serotonin or 5-hydroxytryptamine (5-HT) is a well-reported endogenous autacoid that exerts a plethora of physiological and pathophysiological effects on different organs. 5-HT is released by epithelial enterochromaffin cells upon activation of mucosal processes by both intrinsic and extrinsic primary afferent neurons. 5-HT predominantly mediates signaling to the central nervous system, serotonergic transmission within the enteric nervous system, and the activation of myenteric intrinsic primary afferent neurons. It has seven families of receptors in the brain, numbering at least 14 distinct proteins (Table 1). Although most of the studies concerning its multiple functions in the CNS, high levels of receptor expression in other areas (intestine, platelets, and endothelial cells) suggest that it could play crucial roles in other aspects of physiology [1]. For instance, 5-HT2A has been implicated in the etiology of numerous disease states like neurodysfunction and hypertension, type 2 diabetes mellitus (T2DM), eating disorders, vomiting, and irritable bowel disease (IBD) [2,3,4]. It also regulates cell proliferation, migration, and maturation in a variety of cell types, including renal proximal tubular cells, endothelial cells, mast cells, neurons, and astrocytes. Recent in vitro studies examining 5-HT2 receptors in the kidney have shown the presence of serotonergic 5-HT2A mRNA expression in cultured renal cells, in addition to 5-HT2A protein in renal mesangial cells [5, 6]. Similarly, Banes et al. [7] have also demonstrated the presence of 5-HT2A receptors in vascular smooth muscle cells (VSMCs) [7]. Furthermore, scientific evidence revealed the presence of 5-HT2A receptor mRNA expression in rat renal artery and involvement of renal proximal tubules in the biosynthesis of 5-HT and its storage in the adrenal medulla [8,9,10] (Table 2). Previous reports demonstrated that 5-HT has significant effects on renal metabolism, glomerular function, and renal vascular tone [10, 22]. 5-HT stimulates mitogenesis in rat renal mesangial cells through the 5-HT2A receptor to induce the transcription of mitochondrial genes [23, 24]. Additionally, 5-HT stimulation upregulates PAI-1 expression in proximal tubular epithelial cells, ERK phosphorylation, and cellular proliferation in renal mesangial cells [19, 25]. Generally, the kidney remains protected from hypertensive injury as long as the blood pressure remains within the auto-regulatory range [26]. However, evidence has shown that activation of the 5-HT2A receptor, along with an increase in 5-HT2A receptor density results in an increase in blood pressure [14, 27].

Table 1 Serotonin 5HT2A receptors and their major signaling pathways
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Table 2 Extensively used serotonin 5HT2A receptor modulators in preclinical studies to evaluate the possible role of serotonin 5HT2A receptors in physiology and pathophysiology of CKDs
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Thus, targeting 5-HT2A receptors in nephrotoxic conditions may provide potential therapeutics for various pathological diseases associated with the kidney. However, 5-HT2A-mediated CKDs involve more than single pathological mechanisms. In this review, we have discussed the role and potential mechanisms involving serotonin 5-HT2A receptor-mediated CKDs.

Mechanisms involved in renal pathophysiology

There are several mechanisms proposed by different research groups correlating CKDs and 5-HT receptors.

Autoregulation (intrarenal mechanism)

Renal autoregulation, necessary for the normal renal function and volume homeostasis, has long been a cornerstone of renal physiology. Damage of the vascular smooth muscle cells, acute tubular necrosis, and suppression of vasodilatory autoregulation of renal blood flow (RBF) results in renal dysfunction [8]. Stimulation of 5-HT2 receptors on smooth muscle cells elicits vasoconstriction and further amplifies the vasoconstrictive effects of other chemical mediators [27]. There are enough pieces of evidence that 5-HT is vital for the valid expression of autoregulation of RBF in normal rats [11, 28]. In a renal artery clamp model of ischemic acute renal failure (ARF), 5-HT2-antagonist (ketanserin) treatment showed a beneficial effect on the loss of RBF autoregulation, i.e., administration of ketanserin reduces renal perfusion pressure (RPP) which results in improved autoregulation [13] (Fig. 1). Similarly, Verbeke et al.’s study also states that in cyclosporin A-induced renal dysfunction, autoregulation is suppressed by 5-HT2A-mediated vasoconstriction [14].

Fig. 1
figure 1

Effect of serotonin 5HT2A receptors on renal autoregulation and nitric oxide pathway

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Involvement of NO in 5-HT2A-mediated CKD (intracellular signaling)

Nitric oxide (NO) is one amongst the foremost necessary molecules created within the human body which regulates numerous essential cell functions, including the regulation of healthy blood flow and blood pressure levels. There are two primary pathways for the production of nitric oxide. Nitric oxide synthase (NOS) pathway: Nitric oxide synthase (NOS) is an enzyme found in the endothelial cells, which line blood vessels throughout the body and NOS converts l-arginine into nitric oxide through a series of reaction [29]. Nitrate-nitrite-pathway: Inorganic nitrate, when consumed through diet (i.e., green leafy vegetables such as beets, kale, or spinach), enabled food to be converted into nitrite and nitric oxide by oral bacteria [30].

Several shreds of evidence have reported impaired NOS pathway in animals suffering from CKD-induced [17]. Literature suggests that 5-HT2A receptor activates PLC through Gq and leads to an accumulation of IP3, di-acylglycerol (DAG), and activation of protein kinase C (PKC), and in normal physiological conditions, eNOS is responsible for NO production and further activation of various signaling molecules like increased intracellular cGMP, which inhibits calcium entry into the cell and reduces intracellular calcium concentrations. Followed by activation of K+ channels, which ends up in hyperpolarization and relaxation, stimulates a cGMP-dependent protein enzyme that activates myosin light-chain phosphates via de-phosphorylation of myosin light chains leading to smooth muscle relaxation, and all the abovementioned physiological mechanisms are restored by serotonin 5-HT2A antagonists (sarpogrelate) [19, 31, 32] (Fig. 1). The Umrani et al., in 2003, observed improved NO bioavailability as well as enhanced endothelial eNOS expression in diabetic rats after serotonin antagonist treatment [33].

Mitochondrial damage (intracellular mechanism)

In the renal cortex and renal proximal tubular cells (RPTCs), 5-HT2A receptors are responsible for mitochondrial biogenesis [23], which is a common consequence of ischemia/reperfusion (I/R) injury, drug-induced, toxicant-induced, and oxidant injury. Studies have shown that activation of serotonin 5-HT2A receptors induces transcription of mitochondrial genes and helps to promote recovery of cellular respiration in RPTCs after oxidant injury [34]. 5-HT2A is known to stimulate the release of calcium ions, which further activates cGMP, which is an essential factor for mitochondrial biogenesis [31]. 5-HT2A receptor also induces mitochondrial biogenesis via various signaling pathways, including peroxisome proliferator-activated receptor-γ-coactivator-1α (PPAR-γ-coactivator-1α) by activation of Src, P38 mitogen-activated protein kinase, and epidermal growth factor; cAMP-, calcineurin A-, and calcium/calmodulin-dependent protein kinase. So, these literature reports indicate that modulation of 5-HT2A signaling in the kidney may promote mitochondrial biogenesis [5, 32, 35]. On the contrary, some studies reported that DOI, a specific 5-HT2A agonist, improves the mitochondrial biogenesis after acute or chronic kidney injury [23, 36] (Fig. 2).

Fig. 2
figure 2

Schematic representation of serotonin 5HT2A receptor-mediated mitochondrial biogenesis

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JAK/STAT (intracellular signaling) pathway

JAK/STAT pathway includes a cascade of protein interactions and is associated with immunity, cell death, cell division, and tumor formation. Previous studies have shown that 5-HT2A receptors in vascular smooth muscle cells are involved in the activation of the JAK/STAT pathway. 5-HT2A enhances phosphorylation of JAK2, JAK1, and STAT1 and activates Na+/H+ pump type-I [7]. Activation of JAK/STAT stimulates TGF-β1 and fibronectin synthesis in mesangial cells, which are responsible for increased cellular proliferation and increased DNA synthesis. Enhanced TGF-β1 is a primary pathological marker for proliferative glomerulonephritis, anti-glomerular basement membrane glomerulonephritis, and human renal cell carcinoma [37, 38] (Fig. 3). Furthermore, renal serotonin 5HT2A-mediated JAK/STAT pathway also plays a crucial role in the crosstalk between other signaling cascades like PI3k-Akt (involved in tubulointerstitial fibrosis, glomerulosclerosis results in a progressive decline in kidney functions lead to CKD) [39], EGF-mediated phosphorylation of STAT3, and activation of interleukin-6 (IL-6) [40, 41].

Fig. 3
figure 3

Activation of the JAK/STAT pathway, MCP-1, and adiponectin via stimulation of serotonin 5HT2A receptor

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ERK (extracellular signal-regulated kinase) phosphorylation

Receptor tyrosine kinases are cell surface receptors, which include epidermal growth factor (EGF) receptor (EGFR) [25]. PKC transactivates EGFR in mesangial cells, which helps to regulate the extracellular matrix. Studies have shown that renal mesangial cell expresses mitogenic GPCRs, including angiotensin II, bradykinins, and 5-HT2A receptors, and they all participate in proliferative phases of chronic renal failure. Mesangial cells maintain structural integrity and help in ultrafiltration. Typically, mesangial cells are quiescent but can alter ECM by TGF-β1-mediated proliferation and fibrosis, which leads to irreversible renal injury [6]. 5-HT2A potently activates ERK and induces concentration and time-dependent expression of TGF-β1 mRNA and protein in mesangial cells. 5-HT activation also induces PKC which stimulates NADPH-oxidase and simultaneously increases the expression levels of MEK and ERK [21]. In contrast, serotonin 5-HT2A transactivates EFR and increases collagen IV via PKC and increases cell proliferation (Fig. 4).

Fig. 4
figure 4

Serotonin 5HT2Areceptor activation-mediated oxidative stress, ERK phosphorylation, collagen type IV activation, and alteration in inflammatory cytokines levels

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Collagen type IV (extracellular mechanism)

Collagen type IV is present in basal lamina and reported to be involved in autoimmune disease- (Goodpasture syndrome), in which the immune system attacks the basement membrane of glomeruli and alveoli, and it is also associated with nephritic syndrome and hemoptysis. 5-HT is responsible for the increased induction and secretion of collagen type IV via activation of phospholipase C. Further, this well-known mechanism is linked with enhanced action of DAG and calcium, along with the activation of PKC [20]. Increased response of TGF-β1 is associated with collagen type IV-mediated PKC activation, which further leads to mesangial cell proliferation. Kasho et al., in 1998, reported that the 5-HT2A receptor is responsible for the activation of collagen type IV, and ketanserin (5-HT2A receptor antagonist) could be helpful to overcome the enhanced levels of collagen. Furthermore, several scientific studies suggest that collagen deposition-mediated mesangial cell proliferation and tubulointerstitial fibrosis are major pathogenic factors in the advancement of CKD [20, 42, 43] (Fig. 4). Kim et al. [44] also demonstrated that the activation of serotonin receptors in diabetic mice leads to cortex collagen deposition, and further, the levels of collagen IV and collagen I were consistently reduced by sarpogrelate (5-HT2A receptor antagonist) [45].

Adiponectin (metabolic pathway) and platelets (blood cell-mediated pathway)

Adiponectin is an adipocyte-derived multifunctional peptide which has an anti-inflammatory and anti-atherogenic effect and also involved in insulin sensitization. Studies suggest that higher levels of adiponectin are the indication of progressive CKD and ESRD. The underlying mechanism for adiponectin is found to be related to AMPK and NADPH oxidase-mediated pathway in the kidney. Clinical and preclinical studies suggest that adiponectin levels get reduced in T2DM and obesity [46,47,48,49,50,51,52]. Moreover, in mesenteric adipose tissue, the release of adiponectin is declined via activation of 5-HT2A receptors, and similarly, in genetically modified obese mice, increased 5-HT2A receptor expression levels result in markedly reduced adiponectin levels. Moreover, 5-HT2A receptor knockdown or inhibition of 5-HT2A receptor signaling increases adiponectin expression [53]. Furthermore, scientific studies also supported the fact that 5-HT2A receptor inhibition using sarpogrelate helps to improve early stages of diabetic nephropathy, glomerular endothelial function by increasing adiponectin levels in the blood and reducing albuminuria and glomerular platelet activation in a diabetic animal model [36, 54].

Chronic kidney disease (CKD) is known to associate with numerous hemostatic disorders including increased clotting tendency and defective fibrinolysis due to a decline in natural coagulation inhibitor levels [55,56,57]. Further, during hemodialysis treatment platelet disturbances are commonly aggravated in CKD patients and it is stated that platelets get activated immediately after hemodialysis treatment which is illustrated by upregulation of surface receptors followed by the release of degranulation product results in increased platelet turnover. The release of serotonin from granule stores potentiates activation of platelet further lead to platelet aggregation by recruiting more platelets. [19]. In a similar context, scientific evidences reveal that the release of serotonin from platelet significantly decreases in patients with diabetes mellitus (DM)-associated atherosclerosis and acute and chronic renal failure. Furthermore, the involvement of serotonin (released by platelets) on fibrotic and inflammatory processes in proximal tubular endothelial cells has been explained by Erikci et al. [10]. Proliferation initiates during the healing process of renal tissue platelet aggregates, and neutrophils move towards the injury site and basal epithelial cells. Moreover, serotonin-mediated stimulation of PTECs results in a dose-dependent increase in both TGF-β1 protein levels and relative gene expressions, suggesting the significance of platelet-derived serotonin in the regulation of TGF-β1 and inflammatory mediator levels. Thus, further investigation is required in the delineation of platelet-derived serotonin mechanisms and also in the evaluation of adiponectin impact in progressive CKD.

Inflammatory cytokines, chemokines, and 5-HT2A receptors in CKD

TGF-β1

Transforming growth factor-β (TGF-β) is critical for healthy kidney development and function. Thompson et al. identified TGF-β protein in distal tubular epithelial cells (within the cytoplasm of a subset) at the plasma membranes of cells in the corticomedullary junction in the embryonic murine kidney and the mammalian metanephros during tubular construction. TGF-β stimulation leads to extracellular matrix (ECM) accumulation, activation of many functions in the nearby cells, apoptosis, and cell dedifferentiation followed by loss of function which results in disruption of the orchestrated structural and functional balance of cells [44]. Yang et al., in 2017, reported that 5-HT2A receptors are responsible for the induction of TGF-β1 expression via extracellular signal-regulated kinases, and evidence proves that mitogenic signaling components have a direct relation with TGF-β1 regulation which acts as crucial mediators for proliferation and fibrosis in renal mesangial cells [36]. Schiffer et al. in 2001 presented that TGF-β1 can indirectly affect the permeability properties through apoptosis which is associated with mesangial cell expansion, increased proteinuria, and podocyte depletion [58]. These pathological events are the major hallmark for progressive renal diseases in humans [59, 60], such as glomerulosclerosis [59]and increased expression of cellular ROS.

IL-6 and TNF-α

TNF-α is a cytokine involved in the systemic inflammation, while IL-6 is both a cytokine and a myokine in nature, and their levels get altered during renal complications [61]. Inhibition of TNF-α is responsible for IL-6-mediated anti-inflammatory effect, which also plays a primary role in immune cells, acute-phase reaction, and apoptotic cell death. Kubera et al. [18] have explored the involvement of serotonin receptors in the production of TNF-α and IL-6 by observing the effects of both 5-HT serotonin agonists and antagonists in humans [18]. Their study disclosed that at physiological concentrations, serotonin might partly enhance the production of TNF-α and IL-6 via activation of 5-HT2 receptors, but above the baseline levels, serotonin may suppress the synthesis of these cytokines. Some previous studies have reported a decrease in levels of pro-inflammatory markers as a result of serotonin 5-HT2A receptor antagonism via sarpogrelate hydrochloride [62, 63]. In addition to the determination of the relationship between serotonin receptors and cytokines, IL-6 and TNF-α, dissimilar scientific evidence is also available, suggesting that activation of serotonin by DOI (5-HT2A receptor agonist) leads to inhibition of TNF-α-mediated inflammation and it also inhibits IL-6 [64, 65] (Fig. 4).

MCP-1

MCP-1 is one of the potent chemokines which plays an important role in the kidney, and there are enough pieces of preclinical and clinical evidences describing the role of MCP-1 of renal disease. Inflammation mediated by MCP-1 initiated from the release of monocytes from the bone marrow, and then monocytes migrate towards the site of inflammation via endothelial glycocalyx generated gradient, thereby reducing the migration of blood leukocytes into the inflamed tissue. In addition, MCP-1 has a direct role in migration, proliferation, signaling pathway of monocytes, and differentiation of leukocytes. MCP-1 inhibition is a promising and valid strategy in renal inflammatory disease. Furthermore, several shreds of evidence also reveal the positive correlation between the upregulation of MCP-1 and obesity. Glomerular proteinuria is the postulated link between the increased lysosome and MCP-1 release by PTECs and eventually starts MCP-1-mediated tubulointerstitial fibrosis by stimulating the release of TGF-β via activation of macrophages [66, 67]. Moreover, serotonin-mediated activation of JAK/STAT pathway followed by the activation of monocyte chemoattractant protein-1 (MCP-1), which plays a significant role in macrophage accumulation. However, treatment with 5-HT2A antagonist sarpogrelate was found to be helpful in the recovery of plasma adiponectin levels, maintenance of albumin to Cr ratio, and also MCP-1 levels in the plasma and urine [68].

Oxidative stress

Reactive oxygen species (ROS) are reactive molecules and free radicals derived from molecular oxygen. Recent studies disclosed that renal ROS production in kidney dysfunction is predominantly mediated by various NADPH oxidases (NOXs), mitochondrial dysfunction, NF-κB pathway, and compromised antioxidant system [69,70,71,72]. Kirkman et al., in 2017, observed that mitochondrial dysfunction appeared as a potential source of oxidative stress responsible for the impaired vascular function and mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3–5 CKD [73]. As previous studies suggest, 5-HT2A receptors are involved in the activation and phosphorylation of ERK; during this pathway, reactive oxygen species is generated as intermediate via NADPH [6]. Various clinical and preclinical evidences support the fact that inhibition of 5-HT2A receptor declines the ROS production, enhances the availability of antioxidant enzymes, and as well as helps to improve mitochondrial dysfunction [15, 36]. Kobayashi and his coworkers reported the involvement of 5-HT2A receptors in decreased bioavailability of NO in glomeruli and ROS-mediated endothelial dysfunction in diabetic rats [16]. Upregulation of ROS also results in overexpression of PAI-1 via enhanced levels of TGF-β, which is associated with tubulointerstitial fibrosis, a major pathological event of progressive kidney injury [19] (Fig. 4). 5-HT2A can mediate ROS via mitochondrial oxidative phosphorylation or NADPH oxidases or both.

Clinical relevance of 5-HT receptor modulators in CKD

There are several serotonin modulators available and used for therapeutic purposes, out of which the most popular one is selective serotonin reuptake inhibitors (SSRIs) and are clinically used as anti-depressants. There are clinical pieces of evidence in which sertraline and escitalopram are mentioned to be used cautiously in renal disease patients [74]. On the contrary, some scientific studies suggest that 5-HT2A receptor antagonists help to reduce albuminuria and improve GFR and also long-term outcomes in diabetic patients with early-stage diabetic nephropathy [75, 76]. Bennet et al. in 2015 clinically investigated different gene expressions and enzymes and also conducted transcriptional mapping of 5-HT receptors in diabetes. In results, the author suggested that increased expression of 5-HT1D and 5-HT2A is either cause or consequence of islet dysfunction in type 2 diabetes and alter overall islet hormone secretion in non-diabetic individuals [77]. Additionally, SSRIs have also been studied in depression associated with ESRD and CKD patients [74, 78, 79].

Future perspective for 5-HT2A receptor modulators

A long list of 5-HT2A agonists and antagonists with their respective derivatives has been developed and extensively reviewed. However, most of the drugs are used to evaluate the different mechanisms associated with kidney diseases using cell cultures. Long-term in vivo studies are still needed to do to determine the effect and specific doses of these modulators in chronic therapies. Specific agonists and antagonists, targeting individual PKC mediator for EGFR transactivation will also be helpful. Modern reconstructed lifestyle, patient compliance, MDT (multidrug therapy), and fixed-dose combination therapy will be a positive approach to optimize control of the several risk factors for CKDs. The centerpiece renoprotective treatment for nephropathy-associated proteinuria often includes ACE inhibitors and ARBs. Intriguingly, recent preclinical and clinical findings shown that serotonin antagonism will be useful to avert structural changes and remodeling of the glomerular architecture which offers completely novel perspectives for CKD treatments. However, all the above-listed mechanisms or pathways are interrelated directly or indirectly. Pre- and pro-inflammatory mediators can work as an essential target in every mechanistic pathway associated with CKDs. Furthermore, the number of clinical complications is known to influence different pathological processes of CKDs in various manners. In that case, we have to make a distinct approach to nullify the causes and consequences of CKDs or related complication by using emerging advanced or detailed knowledge of serotonin-mediated pathways.

Conclusion

There is a growing repertoire of proofs supporting the fact that serotonin 5-HT2A receptors are strongly related to the physiological and pathophysiological process of the kidney. Pharmacological inhibition or activation of 5-HT2A-mediated renal autoregulation, mitochondrial biogenesis, inflammatory response via altered pre- or pro-inflammatory cytokines, and accelerated ROS generation and modulation in ERK, MAPK, and JAK/STAT pathways present an appealing therapeutic strategy to attenuate the development of CKDs and renal complications. In conclusion, in the future, with the increasing knowledge of structural systems, all the above-listed pathways, including serotonin 5-HT2A receptor allied with kidney impairment, will provide vital information to explore newer targets, risk factors, and treatment strategies to combat or halt development kidney diseases.

Availability of data and materials

Not applicable

Abbreviations

ARF:

Acute renal failure

CKD:

Chronic kidney disease

DAG:

Di-acylglycerol

EGF:

Epidermal growth factor

ERK:

Extracellular receptor kinase

I/R:

Ischemia/reperfusion

IBD:

Irritable bowel disease

IL:

Interleukin

NO:

Nitric oxide

NOS:

Nitric oxide synthase

NOXs:

NADPH oxidases

PKC:

Protein kinase C

PPAR-γ-coactivator-1α:

Peroxisome proliferator-activated receptor-Γ-coactivator-1α

RBF:

Renal blood flow

ROS:

Reactive oxygen species

RPP:

Renal perfusion pressure

RPTCs:

Renal proximal tubular cells

SSRIs:

Selective serotonin reuptake inhibitors

STAT:

Signal transducer and activator of transcription 3

T2DM :

Type 2 diabetes mellitus

TGF-β:

Transforming growth factor-Β

TNF-α:

Tumor necrosis factor-Α

VSMCs:

Vascular smooth muscle cells

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Acknowledgements

The authors are grateful to the Indian Council of medical research (ICMR) and Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India, for supporting this study.

Funding

The authors are grateful to the Indian Council of Medical Research (ICMR) for funding assistance (Application no: 45/23/2018-PA/BMS/OL)

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  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India

    Gagandeep Kaur & Pawan Krishan

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Correspondence to Pawan Krishan.

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Kaur, G., Krishan, P. Understanding Serotonin 5-HT2A Receptors-regulated cellular and molecular Mechanisms of Chronic Kidney Diseases. Ren Replace Ther 6, 25 (2020). https://doi.org/10.1186/s41100-020-00268-x

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Keywords

Renal Replacement Therapy

ISSN: 2059-1381

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