Part1: Protective Effect Of Hydrogen Sulfide On The Kidney (Review)
May 19, 2022
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Abstract. Hydrogen sulfide(H2S)is a physiologically important gas transmitter that serves various biological functions in the body, in a manner similar to that of carbon monoxide and nitric oxide. Cystathionine-β-synthase, cystathionine-y-lyase, and cysteine transaminase/3-mercaptopyruvate sulphotransferase are important enzymes involved in H2S production in vivo, and the mitochondria are the primary sites of metabolism. It has been reported that H and S serve an important physiological role in the kidney. Under disease conditions, such as ischemia-reperfusion injury, drug nephrotoxicity, and diabetic nephropathy, H2S serves an important role in both the occurrence and development of the disease. The present review aimed to summarize the production, metabolism, and physiological functions of H2S, and the progress in research with regard to its role in renal injury and renal fibrosis in recent years.
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1. Introduction
Hydrogen sulfide (H2S) was initially considered a toxic gas; however, with the continuation of research, it has been revealed to serve an important role in living organisms, becoming another important gas transmitter, alongside carbon monoxide(CO)and nitric oxide(NO)(1,2). Since H2S has been confirmed to be present in mammalian tissues, a large number of studies have suggested that H2S can exert anti-inflammatory, anti-oxidative stress, and anti-fibrotic effects in the body (3,4). Previous studies have confirmed that H, S serves a physiological and pathological role in the cardiovascular system, brain, and nervous system(5-7). However, due to the uneven distribution of H2S-generating enzymes in various organs and tissues, the concentration of H,2S differs widely in different organs (8). The study of the underlying mechanisms of H2S in physiological and pathological processes in the kidney may assist in systematically understanding its molecular biological mechanisms, particularly with regard to its renoprotective role.
2. General physicochemical properties of H2S.
H2S is a colorless gas that smells similar to rotten eggs; the smell of H2S can be picked up by the human olfactory system when the concentration in the air reaches 1/400 of its toxic level (9). As a weak acid, H2S dissociates in water to reach equilibrium at room temperature(25°C)with a pKa, of 6.97-7.06 and pKa, of 12.35-15.0. Moreover, H2S in an aqueous solution is volatile, and its mutual conversion between the liquid phase and the gas phase reaches equilibrium, as shown in Fig.1; this balance is affected by ambient temperature, pressure, and other solutes in the aqueous solution (10).In addition, H2S is highly lipophilic, which not only allows it to have a higher concentration under fat-abundant conditions but also allows it to freely penetrate lipid biofilms without relying on membrane channels to exert its biological activity (11). Since H2S and HS coexist in a solution, it is difficult to make a clear distinction between which of them has a role in biological mechanisms or whether they both have biological effects.
3. Generation and metabolism of H2S
Generation of H2S.The synthesis of H_S in mammals primarily relies on enzymatic pathways. Three traditional enzyme systems that catalyze H2S production include the synergistic action of cystathionine-β-synthase (CBS), cystathionine-y-lyase (CSE), and cysteine transaminase(CAT) with 3-mercaptopyruvate (3-MP) sulphotransferase (3-MST)(12,13). With pyridoxal phosphate (also known as vitamin B6) as a cofactor, CSE and CBS are responsible for the majority of endogenous H2S generated, as shown in Fig.2.L-cysteine is catalyzed by CSE or CBS to produce HS and L-serine, or by CBS to produce pyruvate, NH; and H2S.CSE can polymerize two L-cysteine residues into L-cystine, and then CSE uses L-cystine as a substrate to decompose it into thiocysteine, pyruvate, and NH3. The generated thiocysteine reacts with other thiols to generate H2S through a nonenzymatic reaction. In addition, L-cysteine polymerizes with L-homocysteine as substrates for CSE or CBS to produce L-cystathionine and H2S.L-cystathionine is further decomposed by CSE into L-cysteine,a-ketobutyrate and NH and L-cysteine circulation is achieved(12,13). It has been reported that in the reaction in which L-cysteine is metabolized to H2S via CBS, the amount of H2S produced byβ-replacement is 50X that of β-elimination(14). During the production of H2S by CSE, the α,β-elimination of cysteine is the primary source of HS, accounting for 70% of H2S production(15).
Unlike CSE and CBS, 3-MST uses metallic zinc as a cofactor(14). Moreover, L-cysteine must be converted into 3-MP and L-glutamic acid through the reaction of CAT with α-ketoglutarate, and 3-MP is then desulfurized by 3-MST as a direct substrate to produce HS and pyruvate(16,17).In peroxisomes, D-amino acid oxidase catalyzes D-cysteine, instead of L-cysteine, to produce 3-MP, NH3and H2O, in the presence of water and oxygen, and the resulting 3-MP is transferred to mitochondria for 3-MST utilization to generate H2S(18). The entry of 3-MP in peroxidase into mitochondria is generally in the form of vesicles, as shown in Fig.2. Clinical observations have reported that the synthesis of CSE and CBS in patients with chronic kidney disease is reduced, whereas the expression of 3-MST and hemorrhagic homocysteine is increased(19). This may be explained by the specific mechanism of action used by the aforementioned enzymes to generate H2S. When the production of H2S by CBS and CSE via the L-homocysteine/L-cystathionine pathway is reduced, the utilization of L-homocysteine is restricted, and the patient may present with hyperhomocysteinemia.
Metabolism of H2S. H2S in the body is primarily metabolized by mitochondria(20). Sulfoquinone oxidoreductase (SQOR)in the mitochondria can utilize H2S and metabolize it into thiosulfate with the assistance of thiosulfate sulfurtransferase (TST)and thiol dioxygenase (ETHEl). During this process, reduced glutathione serves an important role, and thiosulfate is further oxidized under the action of thiosulfate reductase and sulfite oxidase(SUOX), and finally excreted in the form of sulfate through the kidneys, as shown in Fig.3.The role of O, in this process, is irreplaceable (21,22). Notably, coenzyme Q(CoQ)is closely related to the aforementioned enzymes. A previous study revealed that the absence of CoQ may induce downregulation of the expression levels of thioquinone oxidoreductase, TST, ETHE1, and SUOX(23). During the early stages of CoQ deficiency, SQOR levels are significantly decreased, affecting H2S oxidation, and CoQ supplementation can save H2S metabolism without affecting its production (24). While SQOR activity and protein levels decrease, protein levels of the other mitochondrial enzymes(TST, ETHEl, and SUOX) in the H2S oxidation pathway increase in fibroblasts; however, it is not clear whether the increase in the levels of several enzymes is a temporary increase in compensation or inversely proportional to the decrease in SQOR levels (23). Therefore, it is important to explore the effect of CoQ deficiency on H2S metabolic enzymes, which may assist in studying the regulation of H2S concentration through H2S metabolic pathways to affect several signaling pathways in the body.
Under normal physiological conditions, when H2S production in tissues exceeds utilization metabolism, another metabolic pathway, cytoplasmic methyltransferase methylation, is required. To date, the known methyltransferases in the human body are thiopurine methyltransferase(TPMT)and thiol methyltransferase(TMT). TPMT selectively methylates thiopurine compounds, whereas TMT selectively methylates aliphatic mercaptan substrates. Using mass spectrometry to directly measure the formation of methyl sulfide, the methylation of H2S and the obtained kinetic curves have previously been assessed; the Km of methylation of HS was 146.2+29.2 μmol（25）. It has also been demonstrated that human methyltransferase-like protein 7B can catalyze the transfer of a methyl group from S-adenosine 1-methionine to H2S and other exogenous mercaptan small molecules, thereby metabolizing H2S (25).In addition, H2S can be removed by methemoglobin or metallic/nonmetallic molecules, such as oxidized glutathione (26).
4. Physiological role of H2S in the kidney
Renal excretory function. Clinical studies have confirmed that plasma H2S levels are positively correlated with glomerular filtration rate in patients with chronic kidney disease (CKD).In addition, serum homocysteine content in patients with advanced CKD(CKD3-5)has been reported to be significantly higher than that in patients with early CKD(CKD1-2), and increases in serum homocysteine levels are associated with the decreased renal function(19). Hyperhomocysteinemia has been shown to aggravate the deposition of extracellular matrix(ECM)proteins and the destruction of connexin, and lead to the phosphorylation of endothelial NO synthase (eNOS)in renal vascular endothelial cells, thereby reducing the bioavailability of NO to induce vasoconstriction and decrease renal blood flow, which is manifested by a decrease in plasma H2S levels and glomerular filtration rate(GFR)(27).H2S can increase urinary sodium and potassium excretion by inhibiting Na-K-2Cl co-transporters and Na-K-ATPase. In vivo experiments have shown that intra-renal artery infusion of the H2S donor NaHS may increase renal blood flow, GFR and excretion of urinary sodium [U(Na)x volume]and potassium [U(K)x volume), and the infusion of L-cysteine via the renal artery to increase the concentration of H2S substrate could simulate this effect (28).In addition, H2S may block the opening of phosphatidylinositol 3,4,5-triphosphate-dependent distal renal epithelial sodium channels induced by H2O, reduce the reabsorption of sodium by nephrons, and increase urinary sodium excretion (29).In addition, the use of CSE and CBS enzyme inhibitors propargylglycine and amino-oxoacetate has been shown to increase urine volume and decrease urine osmotic pressure in mice; this is related to the HS-induced decrease in the expression of aquaporin(AQP)-2 in the renal medulla. Following treatment with GYY4137, an H2S donor sustained release agent, expression levels of AQP-2 were significantly upregulated (30).
H2S can directly target some H2S-sensitive disulfide bonds in the epidermal growth factor receptor(EGFR), which can induce endocytosis and inhibition of Na-K-ATPase in renal tubular epithelial cells by regulating the EGFR/GAB1/PI3K/Akt pathway, thus reducing sodium and potassium ion exchange of renal tubular epithelial cells, and promoting sodium excretion(31). However, how the EGFR/GAB1/PI3K/Akt pathway acts on Na-K-ATPase remains to be determined. EGFR is known to possess tyrosine kinase activity, and its family members can bind to a variety of ligands to form homodimers or heterodimers, leading to the phosphorylation of specific tyrosine residues in intracellular domains. In renal vascular endothelial cells, inhibition of EGFR has been reported to dilate renal vessels and improve renal blood flow; in podocytes, inhibition of EGFR may reduce podocyte damage and loss induced by high glucose levels, and reduce proteinuria, whereas, in renal tubular epithelial cells, inhibition of EGFR was shown to alleviate renal tubular injury and epithelial-mesenchymal transition(EMT)(32,33). However, studies on inhibitors of EGFR tyrosine kinase activity have shown that inhibition of EGFR can also lead to renal tubular damage and electrolyte disturbance(34). Therefore, more in-depth studies are required, particularly with regard to the advantages and disadvantages of H2S in regulating EGFR pathway activity.
Thus, these aforementioned previous studies indicated that H2S has a role in the metabolism of water and electrolytes via a variety of methods. In general, it has been suggested that the increased concentration of H_S is conducive to regulating the excretion of electrolytes by the kidney, whereas the inhibition of its production can preserve sodium drainage. Therefore, H2S-generating enzyme CBS and CSE inhibitors may be potential diuretics.
Oxygen sensing.H2S-mediated O, sense has been detected in various O2-sensing tissues in the cardiovascular and respiratory systems of vertebrates (35,36). The effect of HSon downstream signaling events is consistent with that of hypoxia activation (37,38).In normal kidneys, due to the intrarenal arteriovenous oxygen shunt, the kidney is in a state of low oxygen partial pressure compared with other organs, and the renal medulla oxygen partial pressure is lower than that of the renal parenchyma (39,40). Therefore, H2S is regarded as an oxygen sensor in the kidney, particularly in the medulla (41). As an oxygen sensor, H2S is inseparable from its generation and oxidative metabolic balance.H2S generation is not dependent on O, but its oxidative metabolism in mitochondria is dependent on oxygen, as aforementioned; therefore, hypoxia can lead to an increase in H2S concentration and an inverse relationship exists between the two (37). The mitochondrial oxidative respiratory electron transport chain is the primary means of energy generation; thus it is necessary and significant to prove that H2S participates in energy generation under physiological conditions in the renal medulla under normal hypoxia. As an oxygen sensor, H2S can affect the blood flow supply and regulate the oxygen balance in the heart and lungs. Whether H2S also regulates the distribution of oxygen supply in the renal cortex and medulla under physiological conditions through this mechanism or via other means remains to be determined. Investigating the location and molecular mechanism of H2S as an oxygen sensor affecting the occurrence of downstream signaling events will further enrich our understanding of H2S as an oxygen sensor.
