Part One The Roles Of Hydrogen Sulfide in Renal Physiology And Disease States
Jun 13, 2023
Abstract
Hydrogen sulfide (H2S), an endogenous gaseous signaling transmitter, has gained recognition for its physiological effects. In this review, we aim to summarize and discuss existing studies about the roles of H2S in renal functions and renal disease as well as the underlying mechanisms. H2S is mainly produced by four pathways, and the kidneys are major H2S–producing organs. Previous studies have shown that H2S can impact multiple signaling pathways via sulfhydration. In renal physiology, H2S promotes kidney excretion, regulates renin release, and increases ATP production as a sensor for oxygen. H2S is also involved in the development of kidney disease. H2S has been implicated in renal ischemia/reperfusion and cisplatin-and sepsis-induced kidney disease. In chronic kidney diseases, especially diabetic nephropathy, hypertensive nephropathy, and obstructive kidney disease, H2S attenuates disease progression by regulating oxidative stress, inflammation, and the renin–angiotensin–aldosterone system. Despite accumulating evidence from experimental studies suggesting the potential roles of H2S donors in the treatment of kidney disease, these results need further clinical translation. Therefore, expanding the understanding of H2S can not only promote our further understanding of renal physiology but also lay a foundation for transforming H2S into a target for specific kidney diseases.
Keywords
Hydrogen sulfide; sulfhydration; kidney physiology; acute kidney injury; chronic kidney disease.
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Introduction
Hydrogen sulfide (H2S) is a toxic, colorless gas with an odor of rotten eggs. It exists in nature and can be found in natural gas, volcanic emissions, and petroleum [1]. In 1989, Warenycia and Goodwin [2] first demonstrated that the human body contains H2S, which mainly exists in the brain, and indicated that the brainstem is more sensitive to exogenous H2S than other parts of the brain. The physiological function of H2S has only recently been gradually recognized. High concentrations of H2S may lead to complete inhibition of cell respiration, mitochondrial membrane potential depolarization, and superoxide generation [3]. Low levels of H2S can regulate homeostatic mechanisms such as blood pressure (BP) control and apoptosis and participate in pathological mechanisms including oxidative stress (OS) and inflammation [4,5]. In the kidneys, H2S is actively involved in renal regulation, and H2S production disorders are involved in the onset and development of many kidney diseases [6]. Although exogenous H2S has been shown to play key roles in alleviating various animal models of kidney damage, its specific molecular mechanism is unknown.
In this review, we first describe H2S generation and functions. Next, we introduce the role of H2S in renal physiology. Furthermore, we discuss H2S as a related factor in the occurrence and progression of renal disease and reveal some mechanisms. Finally, we summarize the application of H2S donors and inhibitors in preclinical work and logically evaluate the therapeutic potential of H2S in kidney diseases.
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H2S generation and functions
Although originally viewed as only a toxic gas, H2S is now recognized as a gaseous signaling molecule that is in some ways similar to nitric oxide (NO) and carbon monoxide (CO) [7]. Unlike NO and CO, H2S is acidic, which allows it to dissolve in water. In addition, because H2S is highly lipophilic, it can spread freely to the cell membranes of all cell types [8]. The enzymes responsible for the generation of endogenous H2S include cystathionine–b–synthase (CBS), cystathionine–c–lyase (CSE), and mitochondrial 3–mercaptopyruvate sulfurtransferase (3–MST) [9]. CBS and CSE both produce endogenous H2S in the cytosol, while 3–MST produces endogenous H2S in mitochondria [4,10]. Endogenous H2S is produced in four main ways. In the first mechanism, L–homocysteine and serine produce L–cystathionine under the action of CBS; the L–cystathionine is then changed into L–cysteine by CSE. Finally, H2S is formed in a process mediated by CBS and CSE in the cytoplasm [6]. In the second mechanism, CSE reacts with L–homocysteine to produce H2S, a–ketobutyrate, and L–homolanthionine [4]. In the third mechanism, cysteine aminotransferase converts L–cysteine to 3–mercapto pyruvate (3–MP), which is then utilized by 3–MST for the production of H2S in mitochondria [11]. In the final mechanism, D–amino acid oxidase mediates the transformation of D–cysteine to 3–MP, and H2S is subsequently produced under the action of 3–MST. It is worth noting that 3–MP needs to be imported to mitochondria for the next step. In the kidneys, the main substrate for H2S production is D–cysteine, and H2S from D–cysteine is much more abundant than that from L–cysteine [12] (Figure 1).
Figure 1. Endogenous synthesis of H2S by four pathways. (A) CSE catalyzes the reaction of L–homocysteine to induce the production of H2S. (B) CBS reacts with L–homocysteine, increasing the generation of L–cystathionine, which is then converted into L–cysteine via CSE, which further produces H2S. (C) L–cysteine is converted into 3MP by CAT, and 3–MST catalyzes the reaction of 3MP to induce H2S generation in mitochondria. (D) DAO reacts with D–cysteine to generate 3MP, which then enters mitochondria and serves as a substrate for the production of H2S. CBS (cystathionine b–synthase); CSE (cystathionine c–lyase); CAT (cysteine aminotransferase); 3MP (3–mercapto pyruvate); DAO (D–amino acid oxidase); 3–MST (3–mercapto pyruvate sulfurtransferase).
How does H2S perform biological functions? Recent studies have provided answers. H2S can regulate different signaling pathways that affect cell metabolism. H2S is involved in signal transmission through signaling pathways via sulfhydration, during which it reacts with cysteine residues of various target proteins to form persulfide bonds. The reactivity of sulfhydration is determined by the acid dissociation constants of cysteine residues [13]. Mustafa et al. [14] found that approximately 10–25% of liver proteins can be activated by S–sulfhydration, such as actin, tubulin, and glyceraldehyde–3–phosphate dehydrogenase. S–sulfhydration is essential for the functions of liver proteins; for example, it enhances glyceraldehyde–3–phosphate dehydrogenase activity and actin polymerization. H2S is an endothelium-derived hyperpolarizing factor that can lead to hyperpolarization and vasodilation of vascular endothelial and smooth muscle cells. This vasodilation is mainly achieved via activation of the ATP–sensitive, intermediate, and small conductance potassium channels, and the most critical step for channel activation is S–sulfhydration [15]. H2S participates in inflammatory reactions as a messenger molecule, and the downstream effects of sulfhydration affect nuclear factor jB (NF–jB). NF–jB plays a key role in the inflammatory response in cells. Nil Kantha et al. [5] found that tumor necrosis factor–a (TNF–a) can stimulate the transcription of CSE to generate H2S. H2S sulfhydrates Cys38 of p65, enhancing its binding to the coactivator ribosomal protein S3, thereby regulating the nuclear functions of NF–jB. In CSE–deficient mice, p65 cannot be self-hydrated, resulting in decreased NF–jB target gene activity. The protein tyrosine phosphatase–1B is located on the cytoplasmic face of the endoplasmic reticulum (ER) and has been implicated in ER stress signaling. H2S–induced sulfhydration of protein tyrosine phosphatase–1B participates in the ER stress response [16]. P66Shc is an upstream activator of mitochondrial redox signaling. In response to OS, p66Shc is activated through protein kinase C–bII–mediated phosphorylation at Ser36. Xie et al. [17] found that H2S downregulates the phosphorylation of p66Shc through the sulfhydration of Cys59 residue, thus reducing mitochondrial production of reactive oxygen species (ROS) and achieving antioxidant effects. Nuclear factor–erythroid 2–related factor 2 (Nrf2) is a master regulator of the antioxidant response. Normally, Nrf2 is ubiquitinated and rapidly degraded by the proteasome under the action of Kelch-like ECH–associated protein 1 (Keap1). Sodium sulfide (NaHS) has been reported to be S–sulfhydryl Keap1 at Cys151 and promotes Nrf2 nuclear translocation [18].
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H2S production in the kidneys and its role in kidney physiology
1. H2S production in the kidneys
Some studies have found that the three enzymes that produce endogenous H2S are highly expressed in certain tissues, such as the kidneys [19]. CBS, CSE, and 3–MST can be detected in renal proximal tubules. CSE is also mainly expressed in renal glomeruli, interstitial, and interlobular arteries [19,20]. Under normal conditions, the CSE protein is expressed at the highest level in the kidneys, reaching levels 20 times those of CBS. In the kidney tissues of Sprague–Dawley rats, all three H2S–producing enzymes are present, and CSE mRNA is expressed more abundantly than 3MST and CBS mRNA [4]. Therefore, CSE plays a leading role in the production of H2S [21,22]. CBS and CSE synergistically produce H2S, and these two enzymes can jointly increase the production of endogenous H2S in the kidneys [23].
Three traditional H2S–synthesizing pathways (involving CSE, CBS, and 3–MST coupled with cysteine aminotransferase) have been identified in the kidneys, as described in the “H2S Generation and Functions” section. Therefore, we focused on a fourth H2S generation pathway, namely, the DAO/3–MST pathway [24]. In this pathway, D–cysteine is transformed into 3–MP by peroxisome–located DAO. Due to metabolite exchanges between peroxisomes and mitochondria, 3–MP is imported into mitochondria and catalyzed into H2S by 3–MST [24] (Figure 1). Shibuya et al. showed that kidney lysate can produce 60 times more H2S when D–cysteine is used as a substrate than when L–cysteine is used [12]. The discovery of the unique DAO/3–MST pathway in the kidneys and brain may imply a significant role of 3–MST–mediated H2S generation in these organs. This possibility is worth exploring further.
2. H2S in kidney physiology
2.1. Effect of H2S on renal excretory function
H2S plays an important role in renal excretion. Xia et al. found that both CBS and CSE can produce H2S in the kidney and that when either enzyme is inhibited, the expression of the other increases to compensate. They also found that in anesthetized Sprague–Dawley rats, infusion of NaHS in the renal artery can increase renal blood flow and the glomerular filtration rate (GFR). Because of the increase in the filtration rate, those authors speculated that the role of H2S in vasodilating blood vessels was greater in preglomerular arterioles than in postglomerular arterioles. H2S can also inhibit the Na–K–2Cl cotransporter in the ascending limb of the loop of Henle and the Na–K ATPase enzyme, potentially increasing the excretion of sodium and potassium from urine. Therefore, H2S participates in both vascular and tubular actions in the kidneys [23].
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2.2. H2S as an oxygen sensor
H2S may act as an oxygen (O2) sensor to restore O2 balance, a phenomenon that has been confirmed in various O2–sensing tissues, such as the carotid body, adrenal medulla, and other chemoreceptive tissues, as well as in smooth muscle in systemic and respiratory vessels and airways [25]. H2S metabolism is highly dependent on the concentration of O2 [25]. Under physiological conditions, pO2 is reduced in the renal medulla, and oxidation of H2S is negatively correlated with pO2 in mitochondria, so the activity of H2S in the medulla is likely higher than that in the renal cortex [4]. H2S, which accumulates in increased amounts in the renal medulla under hypoxic conditions, may restore the O2 supply by increasing medullary blood flow [26]. Moreover, studies have shown that under conditions of sufficient oxygen, the levels of CBS and CSE in mitochondria are low. Once hypoxia occurs, the concentrations of CBS and CSE increase, which increases the production of H2S [27,28]. H2S served as an electron donor and increases ATP production [27]. Hypoxia is the most important risk factor for the pathogenesis and progression of many renal diseases. Endogenous H2S deficiency can further contribute to compromised medullary oxygenation and aggravate the occurrence and development of kidney disease [26]. However, the specific mechanism remains unclear and needs further study.
2.3. H2S modulates the renin release
H2S attenuates pathological signaling of the renin-angiotensin-aldosterone system (RAAS) to preserve kidney function. The RAAS is a humoral regulatory system composed of hormones and corresponding enzymes that regulates the excretion of water and sodium. The release of renin from juxtaglomerular cells determines the onset and development of renovascular hypertension, a procedure adjusted by intracellular 30 –50 –cyclic adenosine monophosphate (cAMP). H2S has been reported to downregulate cAMP by inhibiting adenylate cyclase activity, thereby regulating renin release and controlling BP [29,30]. In primary cultures of the renin–rich kidney cells, NaHS significantly reduces the levels of intracellular cAMP and reduces renin activity. In a Dahl rat model of high-salt-induced hypertension, treatment with H2S has been found to inhibit RAAS system activation in the kidneys and regulate BP [31]. H2S also regulates BP via an angiotensin-converting enzyme, which belongs to the RAAS system. In human endothelial cells, H2S can directly interfere with zinc in the active center of the angiotensin-converting enzyme [32].
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In brief, H2S plays a key role in renal physiology; however, further study is required to establish the specific mechanisms involved.
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Jianan Feng, Xiangxue Lu, Han Li, and Shixiang Wang
Department of Nephrology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
