Biomedicine & Pharmacotherapy 166 (2023) 115396
Contents lists available at ScienceDirect 
Biomedicine & Pharmacotherapy 
journal homepage: www.elsevier.com/locate/biopha 
Physiological role of hydrogen sulfide in the kidney and its therapeutic 
implications for kidney diseases 
George J. Dugbartey a,b,* 
a Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, Ghana 
b Accra College of Medicine, Magnolia St, JVX5+FX9, East Legon, Accra, Ghana   
A R T I C L E  I N F O   A B S T R A C T   
Keywords: For over three centuries, hydrogen sulfide (H2S) has been known as a toxic and deadly gas at high concentrations, 
Hydrogen sulfide (H2S) with a distinctive smell of rotten eggs. However, studies over the past two decades have shown that H2S has risen 
Sodium-potassium-ATPase (Na+/K+-ATPase) 
- above its historically notorious label and has now received significant scientific attention as an endogenously Sodium-potassium-chloride (Na+-K+-2Cl ) produced gaseous signaling molecule that participates in cellular homeostasis and influences a myriad of 
cotransporter 
Renal blood flow (RBF) physiological and pathological processes at low concentrations. Its endogenous production is enzymatically 
Glomerular filtration rate (GFR) regulated, and when dysregulated, contributes to pathogenesis of renal diseases. In addition, exogenous H2S 
H2S-producing enzymes administration has been reported to exhibit important therapeutic characteristics that target multiple molecular 
pathways in common renal pathologies in which reduced levels of renal and plasma H2S were observed. This 
review highlights functional anatomy of the kidney and renal production of H2S. The review also discusses 
current understanding of H2S in renal physiology and seeks to lay the foundation as a new targeted therapeutic 
agent for renal pathologies such as hypertensive nephropathy, diabetic kidney disease and water balance 
disorders.   
1. Introduction concentrations. 
H2S is now established among researchers as the third identified 
Hydrogen sulfide (H2S) is a colorless, flammable, membrane- member of a family of gaseous signaling molecules (gasotransmitters) 
permeable and foul-smelling gas that was first described by Bernar- after nitric oxide and carbon monoxide [17–19]. In mammalian cells, 
dino Ramazzini in 1713 as a toxic gas and subsequently established in H2S is enzymatically produced at low physiological and non-toxic con-
the toxicological literature as a fatal gas at high concentrations [1–4]. centrations using the sulfur-containing amino acid, L-cysteine as a 
However, experimental evidence over the past two decades has estab- substrate, and catalyzed by the cytosolic enzymes, cystathionine 
lished a rapid paradigm shift in which H2S functions as an endogenous beta-synthase (CBS) and cystathionine gamma-lyase (CSE) [20] and the 
signaling molecule that participates in cellular homeostasis and in- mitochondrial enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST) 
fluences a myriad of physiological and pathological processes at low [21]. Interestingly, a fourth enzymatic pathway involving the peroxi-
concentrations [5–8]. In addition, low physiological concentrations of somal enzyme, D-amino acid oxidase (DAO) coupled with 3-MST, also 
H2S produce pharmacological effects, affirming the fact that H2S has produces H2S from D-cysteine, a naturally occurring enantiomer of 
successfully overcome its historic notorious label in the toxicological L-cysteine [22] (Fig. 1). 
literature. For example, several studies have shown that H2S exhibits 
antioxidant and anti-inflammatory effects at low concentrations as 2. Effects of hydrogen sulfide on renal physiology 
opposed to pro-oxidant and pro-inflammatory effects at high concen-
trations [9–12]. Also, low H2S concentrations stimulates cellular respi- 2.1. Functional anatomy of the kidney 
ration whereas inhibitory effect on cytochrome c oxidase at high 
concentrations has been well-documented [13–16]. Thus, H2S exerts The kidney is a complex organ and crucial to survival. As a pair, they 
cytoprotection at low concentrations in contrast to cytotoxicity at high are highly vascularized, receiving about 25% of the total cardiac output. 
* Corresponding author at: Department of Pharmacology and Toxicology, School of Pharmacy, College of Health Sciences, University of Ghana, Legon, Accra, 
Ghana. 
E-mail addresses: gjdugbartey@ug.edu.gh, profduu@yahoo.com.  
https://doi.org/10.1016/j.biopha.2023.115396 
Received 21 July 2023; Received in revised form 21 August 2023; Accepted 26 August 2023   
Available online 28 August 2023
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
the tubular system through AQP, except for the thick ascending limb of 
the loop of Henle and the early distal tubule, which are 
water-impermeable. Hence, these two regions are known as the diluting 
segments of the nephron, producing free water (or solute-free water) 
[23]. Surrounding the renal tubules are peritubular capillaries, which 
originate from efferent arteriole, and return the bulk of the solutes and 
water reabsorbed by the tubular system into systemic circulation (i.e. 
the venous system) and conserved for the body’s use. The tubular system 
is also equipped with secretory pathways that dispose of drugs and 
metabolites and other unwanted substances such as creatinine, 
ammonia, urea and uric acid from the peritubular capillaries into the 
glomerular filtrate and excreted in urine [23]. Thus, the elaborate 
reabsorption and secretory pathways modify the composition of the 
glomerular filtrate such that the kidneys produce about 1–2 litres of 
urine per day. 
2.2. Renal production of hydrogen sulfide 
The distribution of all four H2S-producing enzymes is subcellular and 
tissue-specific. In the kidney, however, they are abundantly expressed 
by endothelial cells, mesangial cells, and podocytes within the 
glomeruli, as well as in the brush border and cytoplasm of epithelial cells 
of the renal proximal tubules, distal tubules and in the peritubular 
capillaries, with CBS and CSE being the most dominant. This makes the 
kidney a rich source of endogenous H2S production compared to other 
organs. Using marker enzymes of known localization in a study to 
characterize the renal involvement in homocysteine metabolism, both 
CBS and CSE were reported to be localized in the proximal tubules of rat 
kidneys [26]. While CBS was expressed by proximal tubular cells in the 
outer cortex, CSE was localized in the inner cortex and outer medulla 
[26]. Subsequent studies corroborated this finding using different 
Fig. 1. Simplified view of hydrogen sulfide production in the kidney. (1) H2S methods in mouse and rat kidneys [27–29]. Specifically, both enzymes 
production by CBS using L-cysteine as a substrate; (2) H2S production by CSE are expressed in the brush border and cytoplasm of epithelial cells of the 
using L-cysteine as a substrate; (3) H2S production by 3-MST using L-cysteine as renal proximal tubules, distal tubules and in the peritubular capillaries 
a substrate; (4) H2S production by DAO using D-cysteine as a substrate. H2S, [22,30–34]. In addition to the tubular localization of CBS and CSE, we 
Hydrogen sulfide; CBS, Cystathionine beta-synthase; CSE, Cystathionine also found both enzymes in the glomeruli of rats subjected to hypo-
gamma-lyase; CAT, Cysteine aminotransferase; 3-MST, 3-mercaptopyruvate thermic injury and diabetic nephropathy [35,36]. However, CSE is the 
sulfurtransferase; DAO, D-amino acid oxidase. main H2S-producing enzyme in the glomeruli, which is expressed by 
endothelial cells, mesangial cells and podocytes [32–34]. Besides animal 
They filter about 150–200 liters of fluid daily from renal blood flow kidneys, CSE was also found to be expressed in the glomerular and 
(RBF). This allows for toxins, metabolic waste products, and excess tubulointerstitial compartments of human kidneys [34]. Unlike CBS and 
electrolytes to be excreted while preserving important substances in the CSE, which are the main H2S-synthesizing enzymes in the kidney, 3-MST 
blood that are needed by the body. In addition, the kidneys are actively and DAO have been less studied and their significance in mediating 
involved in water regulation, a role which is supported by high H2S-generating pathways have so far received little scientific attention. 
expression of aquaporins (AQP), integral membrane proteins that serve Nevertheless, they are also expressed in the kidney [22,37,38], with 
as water channels. By regulating body fluids and maintaining electrolyte 3-MST specifically found in epithelial cells of the proximal tubule [38]. 
and acid-base balance, the kidneys regulate blood pressure and ensure In total, about 75% of all renal cells and 87% of endothelial cells express 
normal function of other organs [23–25]. The anatomical and functional H2S-producing enzymes [32,34], making the kidney a rich source of 
unit of the kidney is the nephron, which is divided into two portions, endogenous H2S production and with important roles in renal function. 
namely, the glomerulus (a network of capillary filtration unit) and the This explains why all the known pathways of H2S production have been 
tubular system that is responsible for selective reabsorption and secre- described in the kidney. Interestingly, deficiency in H2S-synthesizing 
tion in the process of urine production. The tubular system is subdivided enzymes and significantly reduced plasma H2S levels have recently been 
into proximal tubule, descending and ascending limbs of loop of Henle, reported in human patients and experimental animals, which correlated 
distal tubule, connecting tubule and collecting duct [23–25]. Following with severity of kidney diseases [39–42]. These findings imply that H2S 
filtration by the glomeruli, the filtrate is transported along the regions of restoration could be a therapeutic target in human kidney diseases. 
the tubular system, where the proximal tubule selectively reabsorbs Fig. 1 is a simplified illustration of endogenous H2S production in the 
about two-thirds of the filtered sodium from the filtrate, a process that is kidney. It is important to note that besides its endogenous production, 
regulated by transmembranal sodium-proton (Na+/H+) antiporter and H2S can also be administered exogenously by inhalation or via H2S 
sodium-potassium-ATPase (Na+/K+-ATPase). Sodium reabsorption also donor compounds to augment endogenous H2S level. These H2S donor 
occurs in the ascending limb of the loop of Henle via the action of compounds include sodium hydrosulfide (NaHS), sodium sulfide (Na2S), 
sodium-potassium-chloride (Na+-K+-2Cl-) cotransporter while sodium sodium thiosulfate, GYY4137, AP39, AP123, SG1002, S-propargyl 
transport in distal tubule is by the actions of sodium-chloride (Na-Cl) cysteine (SPRC; also known as ZYZ-802), sulfurous mineral water and 
cotransporter, and transport in the connecting tubule and collecting duct garlic-derived polysulfide [8,43–47]. 
is under the control of epithelial sodium channel (ENaC) [23]. It is 
important to note that the descending limb of the loop of Henle re-
absorbs water from the glomerular filtrate as well as in other regions of 
2
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
2.3. Hydrogen Sulfide Involvement in Renal Function 
Several lines of empirical evidence have established the involvement 
of H2S in the regulation of cellular physiology via a wide array of 
mechanisms such as regulation of kinases, ion channels and transcrip-
tion factors through post-translational S-sulfhydration of cysteine resi-
dues. H2S also binds to heme in heme-containing proteins, as well as 
functioning as a free radical scavenger and a donor of electrons to the 
mitochondrial electron transport chain to increase mitochondrial ATP 
production and regulate bioenergetics [48–51]. In the kidney, H2S 
functions to regulate many physiological processes including renal 
blood flow, glomerular filtration rate, diuresis, natriuresis kaliuresis, 
and blood pressure. In addition, H2S also functions as an oxygen sensor 
in the renal medulla to ensure oxygen balance and improve medullary 
blood flow. H2S also modulates renin-angiotensin-aldosterone system to 
regulate blood volume, blood pressure and renal hemodynamics. Fig. 2. Effects of H2S on renal function. H2S induces vasodilation and also 
blocks renal tubular transport by inhibiting the activities of Na+/K+-ATPase 
2.3.1. Effect of hydrogen sulfide on renal excretory function and Na+-K+-2Cl- cotransporter, and thereby increasing RBF and GFR, and 
In the kidney, H2S has been shown to alter cellular function in a promoting natriuresis (UNa.V) and kaliuresis (Uk.V). H2S also functions as an 
variety of ways which result in diverse downstream effects. In a porcine oxygen sensor under hypoxic condition in the renal medulla in which its pro-
model of kidney transplantation, for example, infusion of Na2S (an H2S duction increases, leading to oxygen restoration and further enhancing RBF and 
donor) 10 min before and 20 min after reperfusion of cold-stored GFR as well as suppressing tubular transport. H2S, hydrogen sulfide; RBF, renal 
porcine kidneys reversed cyclosporine-induced vasoconstriction and blood flow; GFR, glomerular filtration rate; UNa.V, urinary sodium, Uk.V; 
other pathological changes through increased renal blood flow (RBF) urinary potassium. 
and glomerular filtration rate (GFR; an index of renal clearance func-
tion) [52]. Similarly, in a genetic model of hyperhomocysteinemia (a ability to directly target H2S-sensitive disulfide bonds in epidermal 
risk factor in chronic kidney disease progression), heterozygous CBS growth factor receptor (EGFR) in the proximal tubule, resulting in 
mice (CBS+/-) showed a reduced GFR, which was associated with endocytosis and inhibition of Na+/K+-ATPase via EGFR/GAB1/PI3-
elevated systolic blood pressure and renal dysfunction while GFR was K/Akt signaling pathway [56]. In addition, exogenous H2S administra-
restored, and renal protection observed in CBS+/- mice which received tion prevents hydrogen peroxide-induced activation and opening of 
H2S-suppemented drinking water (30 µM NaHS for 8 weeks) [53]. Also, ENaC in the distal tubule via phosphatidylinositol 3,4,5-trisphosphate 
in a study to determine the effect of H +2S on renal hemodynamics and (PI(3,4,5)P3) pathway [61], and thereby reducing Na reabsorption 
function in rats, intrarenal arterial infusion of NaHS (another H2S donor) and increasing its excretion. There are studies also showing increased 
at a rate of 50 μL/min increased RBF and GFR, and also promoted activity of Cl-/HCO- 3 exchanger in aortic tissues of rats as well in vascular 
natriuresis and kaliuresis, which correlated positively with increased smooth muscle cells [62,63]. Although this has not been studied in the 
plasma H2S level, renal CBS and CSE expression [54]. In addition, kidney, it is possible that H2S exhibits the same effect in renal tissues 
pharmacological inhibition of endogenous H2S with aminooxyacetic considering the crucial role of Cl
-/HCO- 3 exchanger in regulating ion 
acid (AOAA; CBS inhibitor) and propargylglycine (PAG; CSE inhibitor) excretion and maintaining physiological pH. Taken together, H2S in-
together reduced RBF and GFR, resulting in increased Na+ and K+ creases RBF, GFR and excretory function of the kidney by inhibiting the 
reabsorption [54–56]. It is worth noting that failure of the kidney to activities of transporters such as Na+-K+-2Cl- and Na+/K+-ATPase. 
remove excess Na+, for example, is associated with detrimental patho-
logical effects, due to its role in regulating blood volume, fluid balance 2.3.2. Role of hydrogen sulfide in renal water handling 
and blood pressure. In a recent clinical study involving 157 non-dialysis As mentioned in Section 2.1, aquaporins (AQPs), also known as 
patients with chronic kidney disease (CKD), Kung and colleagues [57] water channels, are a family of transmembrane proteins that regulate 
reported that plasma H2S and mRNA levels of CBS and CSE in blood intracellular and intercellular water flow by mediating bi-directional 
mononuclear cells of these patients were significantly lower compared flow of water and small uncharged solutes such as glycerol, urea, 
to healthy controls, which corresponded with reduced GFR and severity ammonia, and hydrogen peroxide down an osmotic gradient, and thus 
of the disease. However, mRNA level of 3-MST was markedly increased influencing the overall process of urine concentration [64]. AQPs are 
in the CKD patients [57], suggesting a compensatory effect between the widely expressed in specific cell types in various tissues. In the kidney, 
H2S-producing enzymes. there are 9 AQPs distributed at various regions of the nephron. They are 
Mechanistically, the increased RBF and GFR by H2S suggests a vas- AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP7, AQP8 and AQP11 [64, 
odilatory effect on afferent arterioles by reducing renal vascular resis- 108]. AQP1 is a highly selective water-permeable channel localized in 
tance possibly via activation of KATP channels (the main vascular target apical and basolateral membrane of the epithelial cells of the proximal 
of H2S), as pharmacological blockade of KATP channels with 10 µM gli- tubules, thin descending limb of loop of Henle and descending vasa recta 
benclamide during renal ischemia-reperfusion injury potentiated further [65] while AQP2 is highly concentrated in the apical membrane of 
injury on renal epithelial integrity in a rat model of isolated perfused collecting duct principal cells (epithelial cells) and involved in regu-
kidney [58]. Also, H2S activates NO/cGMP/sGC/PKG pathway [59,60], lating urine concentration [66]. AQP3 and AQP4 are found in the 
one of the most extensively studied vasodilatory pathways, which basolateral cell membrane of principal collecting duct cells, exporting 
altogether, could account for the increased RBF and GFR in the above water in the cytoplasm [67,68]. AQP5 and AQP6 are localized in 
studies. This also suggests that H2S interacts with other members of the intercalated cells of the collecting duct. However, their functions are not 
gasotransmitter family to induce vasodilation. In the case of increased completely understood [69,70]. AQP 7 is localized in the brush border of 
natriuresis and kaliuresis, H2S administration through NaHS inhibited the S3 segment (straight portion) of the proximal tubule and regulates 
the activities of Na+/K+-ATPase and Na+-K+-2Cl- cotransporter in the glycerol transport, where it mediates glycerol and water transport [71], 
renal tubules [54,56], thereby preventing the reabsorption of these ions whereas AQP8 is found in the epithelial cells of proximal tubule, prin-
and potentiating their excretion (Fig. 2). In a greater detail, the inhibi- cipal cells of collecting duct and mitochondrial membrane, where it 
tory effect of H +2S on Na /K+-ATPase has been shown to be due to its regulates ammonia transport [108]. AQP11 is expressed in the 
3
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
endoplasmic reticulum of epithelial cells of the proximal tubules and osmolality and significantly improved urine concentration [79]. Using 
plays a crucial role in water and glucose reabsorption [72]. Among the an in vitro model, treatment of primary cultured inner medullary col-
renal AQPs, AQP2 is the major regulator of urine concentration, whose lecting duct cells of rats with NaHS and GYY4137 resulted in increased 
function is regulated by arginine vasopressin via activation of intracel- AQP2 protein expression after 5 min of treatment, and was associated 
lular cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) with increased cAMP level in the cell lysate. However, this effect was 
signaling pathway [73,74]. In addition, cAMP response element-binding significantly abrogated with the PKA inhibitor, H89 or adenylyl cyclase 
protein (CREB), a ubiquitously expressed nuclear transcription factor, in rat inner medullary collecting duct suspensions [79]. This result 
has been reported to enhance transcription from AQP2 promoter further affirms the observation that increased renal AQP2 expression 
through cAMP response element [75,76]. It is important to mention that and improvement in urine concentration by H2S is via cAMP/PKA 
PKA phosphorylates AQP2 in addition to other kinases that regulate signaling pathway (Fig. 3). As H2S is an activator cAMP/PKA pathway 
localization of AQP2, and thereby facilitating AQP2 accumulation on under NDI condition, it is important to note that H2S also activates 
the plasma membrane [109]. Interestingly, alteration in AQP2 protein cAMP/PKA signaling pathway in different cell types under different 
expression is associated with water balance disorders such as nephro- conditions [80]. Overall, despite this promising experimental result, the 
genic diabetes insipidus, nephrogenic syndrome of inappropriate anti- finding is from only one study, which makes clinical translation difficult. 
diuresis, syndrome of inappropriate antidiuretic hormone secretion, and Therefore, more studies from other research groups with the same and 
autosomal dominant polycystic kidney disease [77–79]. This finding other H2S donors and at different doses are required to corroborate this 
suggests that vasopressin-AQP2 pathway could be a therapeutic target in result. However, it can be concluded from this single study that H2S 
the treatment and/or pharmacological management of water balance treatment could represent a novel therapy that targets 
disorders, and that urinary AQP2 could serve as a useful biomarker for vasopressin-AQP2 pathway in water balance disorders such as NDI. 
diagnosis of these disorders. 
Burgeoning preclinical evidence shows that H2S upregulates renal 2.3.3. Role of hydrogen sulfide as an oxygen sensor in renal function 
AQP2 expression via cAMP/PKA signaling pathway, and thereby As mentioned in Section 2.1 above, the kidney receives about 25% of 
improving urine concentration in water balance disorders (Fig. 3). In a the total cardiac output. However, the medullary compartment receives 
mouse model of lithium-induced nephrogenic diabetes insipidus (NDI), only about 10% of the total renal perfusion in functionally normal 
a rare water balance disorder characterized by polyuria and polydipsia, kidney due to intrarenal arteriovenous oxygen shunt [81]. This makes 
Luo et al. [79] reported that coadministration of the endogenous H2S the renal medulla highly vulnerable to pathological conditions. Avail-
inhibitors, AOAA (10 mg/kg/d; against CBS) and PAG (30 mg/kg/d; able evidence indicates that H2S is an oxygen sensor and mediates 
against CSE) for 5 days, was associated with a 40% decrease in AQP2 tubulovascular cross-talk in the renal medulla [82–87]. While the pro-
protein expression in the inner medullary collecting duct along with duction of H2S is independent of oxygen, its oxidative metabolism in 
significant downregulation in the expression of renal phosphorylated mitochondria is oxygen-dependent. Thus, the low oxygen partial pres-
CREB (p-CREB) protein compared to control mice. This observation sure in the renal medulla creates a hypoxic environment that leads to 
aligned with marked downregulation of renal AQP2 mRNA expression H2S accumulation, which increases the activity of H2S including electron 
and a 70% reduction in endogenous H2S production in the renal inner donation for ATP production in the mitochondria, and restoration of 
medulla. Similar results were obtained in the renal cortex. In a separate oxygen balance by increasing medullary flow and decreasing tubular 
experiment by the same authors, AOAA and PAG coadministration in Na+ transport, which accounts for 60% of renal oxygen consumption 
dehydrated mice exhibited a 20% decrease in urine osmolality and 25% [55,82–87] (Fig. 2). Considering that majority of Na+-K+-2Cl- channels 
increase in urine production compared to dehydrated control mice. This are found in thick ascending limb of the loop of Henle, which also ex-
corresponded with significant downregulation in AQP2 and p-CREB presses CBS, and requires a balance between oxygen supply and 
protein expression in the renal inner medulla [79], and suggests a urine hyperosmolality for urine concentration [28], the finding that H2S 
concentration defect following endogenous H2S inhibition. However, functions as an oxygen sensor in the renal medulla is very important. 
intraperitoneal administration of the H2S donor, GYY4137 The oxygen-sensing ability of H2S is also supported by the fact that CBS 
(50 mg/kg/d) for 7 days markedly upregulated AQP2 protein expression and CSE translocate into mitochondria under hypoxic conditions to in-
in the renal inner medulla of lithium-induced (NDI) mice compared to crease endogenous H2S production along with 3-MST [13,88]. Besides 
NDI control mice. As expected, this was consistent with increased urine the kidney, H2S-mediating oxygen sensing has also been reported in the 
Fig. 3. Role of H2S in renal water handling. H2S activates intracellular cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway, and 
thereby upregulating renal aquaporin 2 (AQP2) expression. This decreases urine osmolality and improves urine concentration in water balance disorders such as 
nephrogenic diabetes insipidus. 
4
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
heart, lungs and gastrointestinal tract, thus affecting blood flow and H2S in this study was confirmed by another 2K1C rat model in which 
regulating oxygen balance in these tissues [89–91]. However, the spe- daily intraperitoneal administration of 56 µmol/kg of NaHS for 4 weeks 
cific mechanisms and downstream signaling events require further in- inhibited AT1 receptor activation by angiotensin II, reduced systolic 
vestigations. In summary, H2S functions as an oxygen sensor under blood pressure and attenuated ventricular dysfunction, resulting in 
hypoxic conditions, and thereby increasing medullary flow, inhibiting improvement in myocardial remodeling [110]. Using primary cultures 
tubular transport and restoring oxygen balance. of renin-rich kidney cells in a separate experiment, the same authors also 
reported that treatment with 100 μmol/L of NaHS also significantly 
2.3.4. Effect of hydrogen sulfide on intrarenal renin release suppressed renin activity along with reduction in intracellular cAMP 
The renal-angiotensin-aldosterone system (RAAS) is a critical reno- level [102]. This observation was supported by results from later studies 
vascular humoral regulatory system in the body that is composed of in which NaHS (0.1–10 μM) strongly suppressed cAMP production in 
hormones, enzymes, proteins and a series of reactions that regulate As4.1 cells (renin-expressing cell line) treated with isoproterenol (a 
blood volume, blood pressure, renal hemodynamics and systemic β-adrenoceptor agonist), forskolin (an adenylyl cyclase activator), or 
vascular resistance by regulating water, plasma sodium (salt) excretion 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor) by inhib-
and vascular tone on a long-term basis through coordinated effects on iting the activity of adenylyl cyclase (an enzyme that catalyzes the 
the heart, blood vessels and kidneys [92,93]. As a compensatory pro- production of cAMP from ATP), and thus regulating renin activity and 
tective mechanism, the RAAS is activated by a pressure transducer blood pressure [103,104] (Fig. 4). In a model of high-salt-induced hy-
mechanism involving mechanoreceptors in afferent arterioles in pertension in Dahl salt–sensitive rats, feeding on high-salt diet con-
response to conditions such as renal hypoperfusion and hypotension taining 8% NaHS for 8 weeks inhibited RAAS activation in the rat 
(such as during hemorrhage or dehydration) in the early stages of car- kidney, reversed pathological remodeling and prevented salt-sensitive 
diovascular and renal diseases [92,93]. The RAAS is also activated by hypertension, which corresponded with upregulation in renal CBS 
abnormally low concentration of sodium chloride, which is sensed by mRNA and protein expression, 3-MST mRNA expression and signifi-
macula densa cells in the distal convoluted tubule and generate para- cantly increased renal and serum H2S levels to near normal levels 
crine signals in the juxtaglomerular cells present within the walls of the compared to rats fed with high-salt diet without NaHS supplementation 
afferent arterioles of the kidney to release renin [94,95]. However, [105]. Interestingly, H2S had no effect on renin activity in normal rats 
chronic activation of RAAS is pathological, as it produces adverse effects [102], which suggests that H2S only inhibits renin release when RAAS is 
such as syndromes of congestive heart failure, systemic hypertension, overactivated. Using human umbilical vein endothelial cells (a model 
and chronic kidney disease [96,97]. Thus, RAAS activity is determined system for studying endothelial cell function), Laggner et al. [106] also 
and regulated by the release of renin, a process which has been demonstrated that H2S directly inhibits the activity of 
well-documented to be mediated by intracellular cAMP (a second angiotensin-converting enzyme (ACE; a zinc-containing vaso-
messenger in signal transduction) [98–101]. constricting enzyme in the RAAS) in a dose-dependent manner by 
Administration of H2S has been found to modulate renin release interfering with zinc in the active center of ACE (Fig. 4). 
when RAAS is overactivated (Fig. 4). In a two-kidney-one-clip (2K1C) In addition to these experimental models of hypertension, the effect 
model of renovascular hypertension in rats, daily intraperitoneal of H2S on RAAS was also reported in experimental diabetic models. 
administration of 5.6 mg/kg NaHS resulted in significant reduction in Using rat mesangial cells cultured in a medium supplemented with high 
renin activity and levels of angiotensin II (a potent vasoconstrictor in the glucose (25 mM), and streptozotocin-induced diabetic rats, Xue et al. 
RAAS), which positively correlated with downregulation of renal renin [107] observed that high glucose or hyperglycemia downregulated renal 
mRNA and protein expressions as well as blood pressure in 2K1C rats expression of CSE and reduced endogenous H2S production, which 
compared to vehicle control rats [102]. The anti-hypertensive effect of resulted in excessive production of reactive oxygen species (ROS; 
destructive mediator of cell and tissue injury), overactivation of intra-
renal RAAS, and culminated in mesangial cell proliferation and abun-
dant extracellular matrix production. Interestingly, in a separate 
experiment by the same authors, treatment with the CSE inhibitor 
propargylglycine, produced effects similar to that of high-glucose 
treatment [107]. However, treatment with 50 μmol/kg/day of NaHS 
abrogated the high glucose-induced RAAS activation and excess ROS 
production in the renal mesangial cells, and reversed the pathological 
changes associated with overactivation of RAAS, without affecting gly-
cemic status in the diabetic rats [107]. Collectively, these empirical 
findings accentuate the vasodilatory effect of H2S in addition to sup-
pressing RAAS under conditions in which RAAS is overactivated. 
3. Conclusion 
Hydrogen sulfide (H2S), a foul-smelling gas with historic notoriety, 
has recently emerged as an endogenous gaseous signaling molecule that 
plays important roles in cellular homeostasis. The kidney is considered 
one of the major sources of endogenous H2S production due to the 
abundant expression of H2S-producing enzymes in the glomerular and 
tubular compartments, and thereby influencing normal renal function 
such as regulation of renal blood flow, glomerular filtration rate, tubular 
transport, blood pressure, renal bioenergetics and RAAS. Thus, the role 
Fig. 4. H2S modulates renin-angiotensin-aldosterone system (RAAS). Under 
of H2S in renal function implies that it could be considered as a new 
conditions in which RAAS is overactivated, administration of H2S inhibits the therapeutic target or biomarker for renal pathologies such as hyper-
activities of renin and angiotensin-converting enzyme (ACE) as well as reducing tensive nephropathy, diabetic kidney disease and water balance 
angiotensin II level by suppressing intracellular cyclic adenosine mono- disorders. 
phosphate (cAMP) production via inhibition of adenylyl cyclase (AC). 
5
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
CRediT authorship contribution statement [24] G. Giebisch, E. Windhanger, Glomerular filtration and renal blood flow, in: W. 
F. Boron, E.L. Boulpaep (Eds.), Medical Physiology: A Cellular and Molecular 
Approach, Saunders, Philadelphia, 2009, pp. 767–781. 
Conceptualization: GJD; Literature search and collection: GJD [25] A. Bhaskar, V. Oommen, A simple model for demonstrating the factors affecting 
Manuscript writing: GJD; Manuscript review and editing: GJD; glomerular filtration rate, Adv. Physiol. Educ. 42 (2) (2018) 380–382. Jun 01. 
Figure preparation: GJD. [26] J.D. House, M.E. Brosnan, J.T. Brosnan, Characterization of homocysteine 
metabolism in the rat kidney, Biochem J. 328 (Pt 1) (1997) 287–292. Pt 1. 
[27] I. Ishii, N. Akahoshi, X.N. Yu, Y. Kobayashi, K. Namekata, G. Komaki, H. Kimura, 
Declaration of Competing Interest Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, 
promoter activity, tissue distribution and developmental expression, Biochem. J. 
None. 381 (Pt 1) (2004) 113–123. [28] N. Li, L. Chen, R.W. Muh, P.L. Li, Hyperhomocysteinemia associated with 
decreased renal transsulfuration activity in Dahl S rats, Hypertension 47 (2006) 
References 1094–1100. 
[29] P. Tripatara, N.S. Patel, V. Brancaleone, D. Renshaw, J. Rocha, B. Sepodes, 
H. Mota-Filipe, M. Perretti, C. Thiemermann, Characterisation of cystathionine 
[1] B. Ramazzini, The Latin text of 1713, rev. with translation and notes by W.C. gamma-lyase/hydrogen sulphide pathway in ischaemia/reperfusion injury of the 
Wright, University of Chicago Press,, Chicago, IL, 1940, pp. 151–157 (De Morbis mouse kidney: an in vivo study, Eur. J. Pharm. 606 (1–3) (2009) 205–209. 
Anificum Diatriba). [30] J. Yamamoto, W. Sato, T. Kosugi, T. Yamamoto, T. Kimura, S. Taniguchi, et al., 
[2] C.W. Mitchell, S.J. Davenport, Hydrogen sulphide literature, Public Health Rep. Distribution of hydrogen sulfide (H₂S)-producing enzymes and the roles of the 
39 (1924) 1–13. H₂S donor sodium hydrosulfide in diabetic nephropathy, Clin. Exp. Nephrol. 17 
[3] D.S. Gabbay, F. De Roos, J. Perrone, Twenty-foot fall averts fatality from massive (1) (2013) 32–40. 
hydrogen sulfide exposure, J. Emerg. Med 20 (2) (2001) 141–144. [31] M. Xia, L. Chen, R.W. Muh, P.L. Li, N. Li, Production and actions of hydrogen 
[4] R.O. Beauchamp Jr, J.S. Bus, J.A. Popp, C.J. Boreiko, D.A. Andjelkovich, sulfide, a novel gaseous bioactive substance, in the kidneys, J. Pharm. Exp. Ther. 
A critical review of the literature on hydrogen sulfide toxicity, Crit. Rev. Toxicol. 329 (3) (2009) 1056–1062. 
13 (1) (1984) 25–97. [32] H.J. Lee, M.M. Mariappan, D. Feliers, R.C. Cavaglieri, K. Sataranatarajan, H. 
[5] K. Abe, H. Kimura, The possible role of hydrogen sulfide as an endogenous E. Abboud, et al., Hydrogen sulfide inhibits high glucose-induced matrix protein 
neuromodulator, J. Neurosci. 16 (1996) 1066–1071. synthesis by activating AMP-activated protein kinase in renal epithelial cells, 
[6] W. Zhao, J. Zhang, Y. Lu, R. Wang, The vasorelaxant effect of H2S as a novel J. Biol. Chem. 387 (7) (2012) 4451–4461. 
endogenous gaseous KATP channel opener, EMBO J. 20 (2001) 6008–6016. [33] E.M. Bos, H.G. Leuvinink, P.M. Snijder, et al., Hydrogen sulfide-induced 
[7] G. Tang, L. Wu, W. Liang, R. Wang, Direct stimulation of KATP channels by hypometabolism prevents renal ischemia/reperfusion injury, Am. J. Soc. Nephrol. 
exogenous and endogenous hydrogen sulfide in vascular smooth muscle cells, 20 (9) (2009) 1901–1905. 
Mol. Pharm. 68 (2005) 1757–1764. [34] E.M. Bos, R. Wang, P.M. Snijder, et al., Cystathionine γ-lyase protects against 
[8] M.Y. Zhang, G.J. Dugbartey, S. Juriasingani, M. Akbari, W. Liu, A. Haig, renal ischemia/reperfusion by modulating oxidative stress, Am. J. Soc. Nephrol. 
P. McLeod, J. Arp, A. Sener, Sodium thiosulfate-supplemented UW solution 24 (5) (2013) 759–770. 
protects renal grafts against prolonged cold ischemia-reperfusion injury in a [35] G.J. Dugbartey, F. Talaei, M.C. Houwertjes, M. Goris, A.H. Epema, H.R. Bouma, 
murine model of syngeneic kidney transplantation, Biomed. Pharm. 145 (2022), R.H. Henning, Dopamine treatment attenuates acute kidney injury in a rat model 
112435. of deep hypothermia and rewarming - The role of renal H S-producing enzymes, 
[9] Y. Kimura, H. Kimura, Hydrogen sulfide protects neurons from oxidative stress, 2Eur. J. Pharm. 769 (2015) 225–233. 
FASEB J. 18 (2004) 1165–1167. [36] G.J. Dugbartey, K.K. Alornyo, D.E. Diaba, I. Adams, Activation of renal CSE/H S 
[10] M. Whiteman, J.S. Armstrong, S.H. Chu, S. Jia-Ling, B.S. Wong, N.S. Cheung, et 2pathway by alpha-lipoic acid protects against histological and functional changes 
al., The novel neuromodulator hydrogen sulfide: an endogenous peroxynitrite in the diabetic kidney, Biomed. Pharm. 153 (2022), 113386. 
‘scavenger’? J. Neurochem 90 (2004) 765–768. [37] M.A. Aminzadeh, N.D. Vaziri, Downregulation of the renal and hepatic hydrogen 
[11] Y. Kimura, Y. Goto, H. Kimura, Hydrogen sulfide increases glutathione sulfide (H2S)-producing enzymes and capacity in chronic kidney disease, 
production and suppresses oxidative stress in mitochondria, Antioxid. Redox Nephrol. Dial. Transpl. 27 (2) (2012) 498–504. 
Signal 12 (2010) 1–13. [38] N. Nagahara, T. Ito, H. Kitamura, T. Nishino, Tissue and subcellular distribution 
[12] L. Li, M. Bhatia, Y.Z. Zhu, Y.C. Zhu, R.D. Ramnath, Z.J. Wang, et al., Hydrogen of mercaptopyruvate sulfurtransferase in the rat: confocal laser fluorescence and 
sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the immunoelectron microscopic studies combined with biochemical analysis, 
mouse, FASEB J. 19 (2005) 1196–1198. Histochem Cell Biol. 110 (3) (1998) 243–250. 
[13] M. Fu, W. Zhang, L. Wu, G. Yang, H. Li, R. Wang, Hydrogen sulfide (H2S) [39] V. Brancaleone, F. Roviezzo, V. Vellecco, L. De Gruttola, M. Bucci, G. Cirino, 
metabolism in mitochondria and its regulatory role in energy production, Proc. Biosynthesis of H2S is impaired in non-obese diabetic (NOD) mice, Br. J. Pharm. 
Natl. Acad. Sci. USA 109 (2012) 2943–2948. 155 (5) (2008) 673–680. 
[14] M. Goubern, M. Andriamihaja, T. Nübel, F. Blachier, F. Bouillaud, Sulfide, the [40] S.K. Jain, R. Bull, J.L. Rains, P.F. Bass, S.N. Levine, S. Reddy, R. McVie, J. 
first inorganic substrate for human cells, FASEB J. 21 (2007) 1699–1706. A. Bocchini, Low levels of hydrogen sulfide in the blood of diabetes patients and 
[15] C. Szabo, C. Coletta, C. Chao, K. Módis, B. Szczesny, A. Papapetropoulos, et al., streptozotocin-treated rats causes vascular inflammation? Antioxid. Redox Signal 
Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, 12 (11) (2010) 1333–1337. 
stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer, [41] M. Dutta, U.K. Biswas, R. Chakraborty, P. Banerjee, U. Raychaudhuri, A. Kumar, 
Proc. Natl. Acad. Sci. USA 110 (2013) 12474–12479. Evaluation of plasma H S levels and H S synthesis in streptozotocin induced 
[16] K. Módis, C. Coletta, K. Erdélyi, A. Papapetropoulos, C. Szabo, Intramitochondrial 2 2Type-2 diabetes-an experimental study based on Swietenia macrophylla seeds, 
H2S production by 3-mercaptopyruvate sulfurtransferase maintains Asian Pac. J. Trop. Biomed. 4 (1) (2014) S483–S487. 
mitochondrial electron flow and supports cellular bioenergetics, FASEB J. 27 [42] X. Yuan, J. Zhang, F. Xie, W. Tan, S. Wang, L. Huang, L. Tao, Q. Xing, Q. Yuan, 
(2013) 601–611. Loss of the Protein Cystathionine β-Synthase During Kidney Injury Promotes 
[17] P.J. Yates, S.A. Hosgood, M.L. Nicholson, A biphasic response to nitric oxide Renal Tubulointerstitial Fibrosis, Kidney Blood Press Res 42 (3) (2017) 428–443. 
donation in an ex vivo model of donation after cardiac death renal [43] E. Ginter, V. Simko, Garlic (Allium sativum L.) and cardiovascular diseases, 
transplantation, J. Surg. Res 175 (2) (2012) 316–321. Bratisl. Lek. Listy 111 (8) (2010) 452–456. 
[18] G.J. Dugbartey, K.K. Alornyo, P.P.W. Luke, A. Sener, Application of carbon [44] K. Kashfi, K.R. Olson, Biology and therapeutic potential of hydrogen sulfide and 
monoxide in kidney and heart transplantation: A novel pharmacological strategy hydrogen sulfide-releasing chimeras, Biochem Pharm. 85 (5) (2013) 689–703. 
for a broader use of suboptimal renal and cardiac grafts, Pharm. Res 173 (2021), [45] M.M. Safar, R.M. Abdelsalam, H2S donors attenuate diabetic nephropathy in rats: 
105883. Modulation of oxidant status and polyol pathway, Pharm. Rep. 67 (1) (2015) 
[19] G.J. Dugbartey, Carbon monoxide as an emerging pharmacological tool to 17–23. 
improve lung and liver transplantation protocols, Biochem Pharm. 193 (2021), [46] D. Gerő, R. Torregrossa, A. Perry, A. Waters, S. Le-Trionnaire, J.L. Whatmore, 
114752. M. Wood, M. Whiteman, The novel mitochondria-targeted hydrogen sulfide (H2S) 
[20] R. Hosoki, N. Matsuki, H. Kimura, The possible role of hydrogen sulfide as an donors AP123 and AP39 protect against hyperglycemic injury in microvascular 
endogenous smooth muscle relaxant in synergy with nitric oxide, Biochem endothelial cells in vitro, Pharm. Res. 113 (Pt A) (2016) 186–198. 
Biophys. Res Commun. 237 (1997) 527–531. [47] D.J. Polhemus, Z. Li, C.B. Pattillo, G.Sr Gojon, G.Jr Gojon, T. Giordano, H. Krum, 
[21] N. Shibuya, M. Tanaka, M. Yoshida, Y. Ogasawara, T. Togawa, K. Ishii, H. Kimura, A novel hydrogen sulfide prodrug, SG1002, promotes hydrogen sulfide and nitric 
3-Mercaptopyruvate sulfurtransferease produces hydrogen sulfide and bound oxide bioavailability in heart failure patients, Cardiovasc Ther. 33 (4) (2015) 
sulfane sulfur in the brain, Antioxid. Redox Signal 11 (2009) 703–714. 216–226. 
[22] N. Shibuya, S. Koike, M. Tanaka, M. Ishigami-Yuasa, Y. Kimura, Y. Ogasawara, [48] A.K. Mustafa, M.M. Gadalla, N. Sen, S. Kim, W. Mu, S.K. Gazi, R.K. Barrow, 
K. Fukui, N. Nagahara, H. Kimura, A novel pathway for the production of G. Yang, R. Wang, S.H. Snyder, H2S signals through protein S-sulfhydration, Sci. hydrogen sulfide from D-cysteine in mammalian cells, Nat. Commun. 4 (2013) Signal 2 (96) (2009) ra72. 
1366. [49] O. Kabil, R. Banerjee, Redox biochemistry of hydrogen sulfide, J. Biol. Chem. 285 
[23] D.C. Eaton, J.P. Pooler. Vanders Renal Physiology, ninth ed., McGraw Hill (29) (2010) 21903–21907. 
Publisher, 2018. [50] Y.H. Liu, C.D. Yan, J.S. Bian, Hydrogen sulfide: a novel signaling molecule in the 
vascular system, J. Cardiovasc Pharm. 58 (6) (2011) 560–569. 
6
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
[51] M. Fu, W. Zhang, L. Wu, G. Yang, H. Li, R. Wang, Hydrogen sulfide (H2S) [79] R. Luo, S. Hu, Q. Liu, M. Han, F. Wang, M. Qiu, S. Li, X. Li, T. Yang, X. Fu, 
metabolism in mitochondria and its regulatory role in energy production, Proc. W. Wang, C. Li, Hydrogen sulfide upregulates renal AQP-2 protein expression and 
Natl. Acad. Sci. USA 109 (8) (2012) 2943–2948. promotes urine concentration, FASEB J. 33 (1) (2019) 469–483. 
[52] G. Lee, S.A. Hosgood, M.S. Patel, M.L. Nicholson, Hydrogen sulphide as a novel [80] W. Zhao, R. Wang, H2S-induced vasorelaxation and underlying cellular and 
therapy to ameliorate cyclosporine nephrotoxicity, J. Surg. Res 197 (2015) molecular mechanisms, Am. J. Physiol. Heart Circ. Physiol. 283 (2002) 
419–426. H474–H480. 
[53] S. Pushpakumar, S. Kundu, U. Sen, Hydrogen Sulfide Protects [81] M. Maruno, H. Kiyosue, S. Tanoue, N. Hongo, S. Matsumoto, H. Mori, et al., Renal 
Hyperhomocysteinemia-Induced Renal Damage by Modulation of Caveolin and arteriovenous shunts: Clinical features, imaging appearance, and transcatheter 
eNOS Interaction, Sci. Rep. 9 (1) (2019) 2223. embolization based on angioarchitecture, Radiographics 36 (2) (2016) 580–595. 
[54] M. Xia, L. Chen, R.W. Muh, P.L. Li, N. Li, Production and actions of hydrogen [82] K.R. Olson, R.A. Dombkowski, M.J. Russell, M.M. Doellman, S.K. Head, N. 
sulfide, a novel gaseous bioactive substance, in the kidneys, J. Pharm. Exp. Ther. L. Whitfield, J.A. Madden, Hydrogen sulfide as an oxygen sensor/transducer in 
329 (3) (2009) 1056–1062. vertebrate hypoxic vasoconstriction and hypoxic vasodilation, J. Exp. Biol. 209 
[55] A. Roy, A.H. Khan, M.T. Islam, M.C. Prieto, D.S. Majid, Interdependency of (Pt 20) (2006) 4011–4023. 
cystathione γ-lyase and cystathione β-synthase in hydrogen sulfide-induced blood [83] A.M. Koning, A.R. Frenay, H.G. Leuvenink, H. van Goor, Hydrogen sulfide in 
pressure regulation in rats, Am. J. Hypertens. 25 (1) (2012) 74–81. renal physiology, disease and transplantation–the smell of renal protection, Nitric 
[56] S.N. Ge, M.M. Zhao, D.D. Wu, Y. Chen, Y. Wang, J.H. Zhu, W.J. Cai, Y.Z. Zhu, Y. Oxide 46 (2015) 37–49. 
C. Zhu, Hydrogen sulfide targets EGFR Cys797/Cys798 residues to induce Na(+)/ [84] J. Bełtowski, Hypoxia in the renal medulla: implications for hydrogen sulfide 
K(+)-ATPase endocytosis and inhibition in renal tubular epithelial cells and signaling, J. Pharm. Exp. Ther. 334 (2) (2010) 358–363. 
increase sodium excretion in chronic salt-loaded rats, Antioxid. Redox Signal 21 [85] K.R. Olson, Hydrogen sulfide as an oxygen sensor, Antioxid. Redox Signal 22 (5) 
(15) (2014) 2061–2082. (2015) 377–397. 
[57] Q. Kuang, N. Xue, J. Chen, Z. Shen, X. Cui, Y. Fang, X. Ding, Low Plasma [86] K.R. Olson, Hydrogen sulfide as an oxygen sensor, Clin. Chem. Lab Med 51 (3) 
Hydrogen Sulfide Is Associated with Impaired Renal Function and Cardiac (2013) 623–632. 
Dysfunction, Am. J. Nephrol. 47 (5) (2018) 361–371. [87] J. Prieto-Lloret, P.I. Aaronson, Hydrogen Sulfide as an O2 Sensor: A Critical 
[58] M. Rahgozar, D.A. Willgoss, G.C. Gobé, Z.H. Endre, ATP-dependent K+ channels Analysis, Adv. Exp. Med Biol. 967 (2017) 261–276. 
in renal ischemia reperfusion injury, Ren. Fail 25 (6) (2003) 885–896. [88] H. Teng, B. Wu, K. Zhao, G. Yang, L. Wu, R. Wang, Oxygen-sensitive 
[59] R. Wang, Signaling pathways for the vascular effects of hydrogen sulfide, Curr. mitochondrial accumulation of cystathionine β-synthase mediated by Lon 
Opin. Nephrol. Hypertens. 20 (2011) 107–112. protease, Proc. Natl. Acad. Sci. USA 110 (31) (2013) 12679–12684. 
[60] R. Wang, C. Szabo, F. Ichinose, A. Ahmed, M. Whiteman, A. Papapetropoulos, The [89] K.R. Olson, N.L. Whitfield, Hydrogen sulfide and oxygen sensing in the 
role of H2S bioavailability in endothelial dysfunction, Trends Pharm. Sci. 36 cardiovascular system, Antioxid. Redox Signal 12 (10) (2010) 1219–1234. 
(2015) 568–578. [90] H. Hu, Y. Shi, Q. Chen, W. Yang, H. Zhou, L. Chen, Y. Tang, Y. Zheng, Endogenous 
[61] J. Zhang, S. Chen, H. Liu, B. Zhang, Y. Zhao, K. Ma, D. Zhao, Q. Wang, H. Ma, hydrogen sulfide is involved in regulation of respiration in medullary slice of 
Z. Zhang, Hydrogen sulfide prevents hydrogen peroxide-induced activation of neonatal rats, Neuroscience 156 (4) (2008) 1074–1082. 
epithelial sodium channel through a PTEN/PI(3,4,5)P3 dependent pathway, PLoS [91] R.A. Dombkowski, M.G. Naylor, E. Shoemaker, M. Smith, E.R. DeLeon, G.F. Stoy, 
One 8 (5) (2013), e64304. Y. Gao, K.R. Olson, Hydrogen sulfide (H₂S) and hypoxia inhibit salmonid 
[62] Y.H. Liu, J.S. Bian, Bicarbonate-dependent effect of hydrogen sulfide on vascular gastrointestinal motility: evidence for H₂S as an oxygen sensor, J. Exp. Biol. 214 
contractility in rat aortic rings, Am. J. Physiol. Cell Physiol. 299 (4) (2010) (Pt 23) (2011) 4030–4040. 
C866–C872. [92] T. Yang, C. Xu, Physiology and Pathophysiology of the Intrarenal Renin- 
[63] S.W. Lee, Y. Cheng, P.K. Moore, J.S. Bian, Hydrogen sulphide regulates Angiotensin System: An Update, J. Am. Soc. Nephrol. 28 (4) (2017) 1040–1049. 
intracellular pH in vascular smooth muscle cells, Biochem Biophys. Res Commun. [93] J.H. Fountain, J. Kaur, S.L. Lappin, Physiology, Renin Angiotensin System, 
358 (4) (2007) 1142–1147. StatPearls Publishing,, StatPearls. Treasure Island (FL), 2023. 
[64] Y. Li, W. Wang, T. Jiang, B. Yang, Aquaporins in urinary system, Adv. Exp. Med [94] S.L. Vargas, I. Toma, J.J. Kang, E.J. Meer, J. Peti-Peterdi, Activation of the 
Biol. 969 (2017) 131–148. succinate receptor GPR91 in macula densa cells causes renin release, J. Am. Soc. 
[65] C.L. Chou, M.A. Knepper, A.N. Hoek, D. Brown, B. Yang, T. Ma, A.S. Verkman, Nephrol. 20 (5) (2009) 1002–1011. 
Reduced water permeability and altered ultrastructure in thin descending limb of [95] J. Peti-Peterdi, R.C. Harris, Macula densa sensing and signaling mechanisms of 
Henle in aquaporin-1 null mice, J. Clin. Invest 103 (4) (1999) 491–496. renin release, J. Am. Soc. Nephrol. 21 (7) (2010) 1093–1096. 
[66] H. Ren, B. Yang, P.A. Molina, J.M. Sands, J.D. Klein, NSAIDs alter phosphorylated [96] G. Remuzzi, N. Perico, M. Macia, P. Ruggenenti, The role of renin-angiotensin- 
forms of AQP2 in the Inner Medullary Tip, PLoS One 10 (10) (2015), e0141714. aldosterone system in the progression of chronic kidney disease, Kidney Int Suppl. 
[67] T. Ma, Y. Song, B. Yang, A. Gillespie, E.J. Carlson, C.J. Epstein, A.S. Verkman, 99 (2005) S57–S65. 
Nephrogenic diabetes insipidus in mice lacking aquaporin-3 water channels, Proc. [97] M.K. Ames, C.E. Atkins, B. Pitt, The renin-angiotensin-aldosterone system and its 
Natl. Acad. Sci. USA 97 (8) (2000) 4386–4391. suppression, J. Vet. Intern Med 33 (2) (2019) 363–382. 
[68] Y.H. Kim, J.H. Earm, T. Ma, A.S. Verkman, M.A. Knepper, K.M. Madsen, J. Kim, [98] J. Peters, K. Münter, M. Bader, E. Hackenthal, J.J. Mullins, D. Ganten, Increased 
Aquaporin-4 expression in adult and developing mouse and rat kidney, J. Am. adrenal renin in transgenic hypertensive rats, TGR(mREN2)27, and its regulation 
Soc. Nephrol. 12 (9) (2001) 1795–1804. by cAMP, angiotensin II, and calcium, J. Clin. Invest 91 (3) (1993) 742–747. 
[69] G. Procino, L. Mastrofrancesco, F. Sallustio, V. Costantino, C. Barbieri, F. Pisani, [99] S. Gambaryan, C. Wagner, A. Smolenski, U. Walter, W. Poller, W. Haase, A. Kurtz, 
F.P. Schena, M. Svelto, G. Valenti, AQP5 is expressed in type-B intercalated cells S.M. Lohmann, Endogenous or overexpressed cGMP-dependent protein kinases 
in the collecting duct system of the rat, mouse and human kidney, Cell Physiol. inhibit cAMP-dependent renin release from rat isolated perfused kidney, 
Biochem 28 (4) (2011) 683–692. microdissected glomeruli, and isolated juxtaglomerular cells, Proc. Natl. Acad. 
[70] D. Promeneur, T.H. Kwon, M. Yasui, G.H. Kim, J. Frøkiaer, M.A. Knepper, P. Agre, Sci. USA 95 (15) (1998) 9003–9008. 
S. Nielsen, Regulation of AQP6 mRNA and protein expression in rats in response [100] U.G. Friis, B.L. Jensen, S. Sethi, D. Andreasen, P.B. Hansen, O. Skott, Control of 
to altered acid-base or water balance, Am. J. Physiol. Ren. Physiol. 279 (6) (2000) renin secretion from rat juxtaglomerular cells by cAMP-specific 
F1014–F1026. phosphodiesterases, Circ. Res 90 (2002) 996–1003. 
[71] K. Ishibashi, M. Imai, S. Sasaki, Cellular localization of aquaporin 7 in the rat [101] U.G. Friis, J. Stubbe, T.R. Uhrenholt, P. Svenningsen, R.M. Nusing, O. Skøtt, B. 
kidney, Exp. Nephrol. 8 (4–5) (2000) 252–257. L. Jensen, Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP- 
[72] E.N. Atochina-Vasserman, A. Biktasova, E. Abramova, D.S. Cheng, V. dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells, 
V. Polosukhin, et al., Aquaporin 11 insufficiency modulates kidney susceptibility Am. J. Physiol. Ren. Physiol. 289 (2005) F989–F997. 
to oxidative stress, Am. J. Physiol. Ren. Physiol. 304 (10) (2013) F1295–F1307. [102] M. Lu, Y.H. Liu, H.S. Goh, J.J. Wang, Q.C. Yong, R. Wang, J.S. Bian, Hydrogen 
[73] H. Ren, B. Yang, J.A. Ruiz, O. Efe, T.O. Ilori, J.M. Sands, J.D. Klein, Phosphatase sulfide inhibits plasma renin activity, J. Am. Soc. Nephrol. 21 (6) (2010) 
inhibition increases AQP2 accumulation in the rat IMCD apical plasma 993–1002. 
membrane, Am. J. Physiol. Ren. Physiol. 311 (6) (2016) F1189–F1197. [103] M. Lu, Y.H. Liu, C.Y. Ho, C.X. Tiong, J.S. Bian, Hydrogen sulfide regulates cAMP 
[74] L. Lei, M. Huang, L. Su, D. Xie, F.A. Mamuya, O. Ham, K. Tsuji, T.G. Păunescu, homeostasis and renin degranulation in As4.1 and rat renin-rich kidney cells, Am. 
B. Yang, H.A.J. Lu, Manganese promotes intracellular accumulation of AQP2 via J. Physiol. Cell Physiol. 302 (1) (2012) C59–C66. 
modulating F-actin polymerization and reduces urinary concentration in mice, [104] Y.H. Liu, M. Lu, Z.Z. Xie, F. Hua, L. Xie, J.H. Gao, Y.H. Koh, J.S. Bian, Hydrogen 
Am. J. Physiol. Ren. Physiol. 314 (2) (2018) F306–F316. sulfide prevents heart failure development via inhibition of renin release from 
[75] Y. Matsumura, S. Uchida, T. Rai, S. Sasaki, F. Marumo, Transcriptional regulation mast cells in isoproterenol-treated rats, Antioxid. Redox Signal 20 (5) (2014) 
of aquaporin-2 water channel gene by cAMP, J. Am. Soc. Nephrol. 8 (6) (1997) 759–769. 
861–867. [105] P. Huang, S. Chen, Y. Wang, J. Liu, Q. Yao, Y. Huang, H. Li, M. Zhu, S. Wang, L. Li, 
[76] H.J. Jung, V. Raghuram, J.W. Lee, M.A. Knepper, Genome-Wide Mapping of DNA C. Tang, Y. Tao, G. Yang, J. Du, H. Jin, Down-regulated CBS/H2S pathway is 
Accessibility and Binding Sites for CREB and C/EBPβ in Vasopressin-Sensitive involved in high-salt-induced hypertension in Dahl rats, Nitric Oxide 46 (2015) 
Collecting Duct Cells, J. Am. Soc. Nephrol. 29 (5) (2018) 1490–1500. 192–203. 
[77] M. Ranieri, A. Di Mise, G. Tamma, G. Valenti, Vasopressin-aquaporin-2 pathway: [106] H. Laggner, M. Hermann, H. Esterbauer, M.K. Muellner, M. Exner, B.M. Gmeiner, 
recent advances in understanding water balance disorders, F1000Res. 8 (2019). S. Kapiotis, The novel gaseous vasorelaxant hydrogen sulfide inhibits angiotensin- 
F1000 Faculty Rev-149. converting enzyme activity of endothelial cells, J. Hypertens. 25 (10) (2007) 
[78] G. Valenti, G. Tamma, The vasopressin-aquaporin-2 pathway syndromes, Handb. 2100–2104. 
Clin. Neurol. 181 (2021) 249–259. [107] H. Xue, P. Yuan, J. Ni, C. Li, D. Shao, J. Liu, Y. Shen, Z. Wang, L. Zhou, W. Zhang, 
Y. Huang, C. Yu, R. Wang, L. Lu, H(2)S inhibits hyperglycemia-induced intrarenal 
7
G.J. Dugbartey                                                                                                                                                                                    B  i o  m   e d  i c i n  e   &   P  h  a  r m  a  c  o t h  e  r a  p y  166 (2023) 115396
renin-angiotensin system activation via attenuation of reactive oxygen species [110] S.Y. Liu, X.C. Duan, S. Jin, X. Teng, L. Xiao, H.M. Xue, Y.M. Wu, Hydrogen Sulfide 
generation, PLoS One 8 (9) (2013), e74366. Improves Myocardial Remodeling via Downregulated Angiotensin II/AT1R 
[108] W. Su, R. Cao, X.Y. Zhang, Y. Guan, Aquaporins in the kidney: physiology and Pathway in Renovascular Hypertensive Rats, Am. J. Hypertens. 30 (1) (2017) 
pathophysiology, Am. J. Physiol. Ren. Physiol. 318 (1) (2020) F193–F203. Jan 1. 67–74. 
[109] A. Kharin, E. Klussmann, Many kinases for controlling the water channel 
aquaporin-2, J. Physiol. (2023), https://doi.org/10.1113/JP284100. 
8