Protective effect of hydrogen sulfide on the kidney (Review)

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‑γ‑lyase and cysteine transaminase/3‑mercaptopyruvate sulphotransferase are important enzymes involved H₂S production in vivo, and the mitochondria are the primary sites of metabolism. It has been reported that H₂S serves 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 regards to its role in renal injury and renal fibrosis in recent years.

Keywords: diabetic nephropathy; drug nephrotoxicity; hydrogen sulfide; ischemia‑reperfusion injury; renal fibrosis.

Figure 1.

Dissociation equilibrium of H2S in aqueous solution (25°C). K₁ and K₂ represent the equilibrium constants when H₂S and HS reach dissociation equilibrium in aqueous solution, respectively. H₂S, hydrogen sulfide; g, gaseous; aq, aqueous.

Figure 2.

In the cytoplasm, 1–3: CSE or CBS catalyzes the β-replacement reaction of L-cysteine and L-homocysteine to polymerize and form L-cystathionine and H₂S. L-cystathionine is decomposed by CSE into L-cysteine, α-ketobutyrate and NH₃ by means of α, γ-elimination. L-cysteine continues to participate in the reaction. 4 and 5: L-cysteine is catalyzed to produce L-serine and H₂S via CBS β-elimination or CSE α, β-elimination. 7: CBS catalyzes L-cysteine to produce pyruvate, NH₃ and H₂S through α, β-elimination. 6 and 9: CSE first polymerizes two L-cysteines into L-cystine, then CSE uses L-cystine as a substrate to decompose it into thiocysteine (mercaptocysteine, Cyc-SSH), pyruvate and NH₃, resulting in thiocysteine generating H₂S via nonenzymatic reactions with other thiols. 8: L-homocysteine generates α-ketobutyrate, NH₃ and H₂S through CSE α, γ-elimination. In the mitochondria, CAT catalyzes L-cysteine and α-ketoglutarate to produce 3-MP, which is then catalyzed by 3-MST to produce pyruvate and H₂S. In peroxisomes, 3-MP produced by DAO and catalyzed by D-cysteine is transported to the mitochondria in vesicles. H₂S, hydrogen sulfide; CBS, cystathionine-β-synthase; CSE, cystathionine-γ-lyase; 3-MP, 3-mercaptopyruvate; CAT, cysteine transaminase; 3-MST, 3-MP sulphotransferase; DAO, D-amino acid oxidase.

Figure 3.

Oxidative metabolism of H₂S in the mitochondria. H₂S in the mitochondria is activated by SQOR, which receives an-SH group to form an-SSH group. In the presence of O₂ and H₂O, -SSH is used by ETHE1 to generate H₂SO₃, which is further converted into thiosulfate by TST using the-SSH group. Finally, thiosulfate is oxidized by TR and SUOX, and is eventually excreted in the kidney as sulfate. H₂S, hydrogen sulfide; SQOR, sulfoquinone oxidoreductase; ETHE1, thiodioxygenase; TST, thiosulfate sulfur transferase; TR, thiosulfate reductase; SUOX, sulfite oxidase.

Figure 4.

H₂S and renal injury. In the mitochondria, H₂S increases S-mercaptoylation of the four cysteine residues of SIRT3, and induces deacetylation of its target proteins, OPA1, ATP synthase (depicted as ATP in the figure) and SOD2, thus reducing mitochondrial division and increasing ATP production. H₂S reduces MPTP opening and loss of mitochondrial membrane potential via Ca²⁺-dependent CypD activation by inhibiting NMDA-R1 mediated Ca²⁺ influx, thus avoiding mitochondrial morphological and functional damage, leading to ROS accumulation. ROS leads to the peroxidation of membrane lipids to MDA, causing damage to cells and organelles. The prevulcanization of H₂S on NADPH oxidase subunit P47PHOx inhibits the activity of NADPH oxidase, thereby inhibiting the generation of MAPKs and intracellular ROS. H₂S leads to the phosphorylation of AKT and dimerization of Keap1, and induces nuclear translocation of Nrf2 to promote the expression of antioxidant substances, thereby inhibiting ROS in cells. NaHS downregulates the overexpression of renal iNOS, upregulates eNOS and HO-1, and regulates the T-AOC and IL-10 via the CO/NO pathway to exert an anti-inflammatory and antioxidant effect. H₂S, hydrogen sulfide; OPA1, dynamin-like 120 kDa protein; SIRT3, NAD-dependent deacetylase sirtuin-3; SOD2, superoxide dismutase 2; MPTP, mitochondrial permeability transition pore; iNOS, inducible nitric oxide synthase; eNOS, endothelial nitric oxide synthase; HO-1, heme oxygenase-1; T-AOC, total antioxidant capacity; Nrf2, nuclear factor erythroid 2-related factor 2; Keap1, Kelch-like ECH-related protein 1; ROS, reactive oxygen species; TLR, Toll-like receptor; CBS, cystathionine-β-synthase; CSE, cystathionine-γ-lyase; p-, phosphorylated; MDA, malondialdehyde; CO, carbon monoxide; NO, nitric oxide.

Figure 5.

H₂S and renal fibrosis. TGF-β1 binds to TβR and promotes downstream Smad protein activation, leading to the overexpression of fibronectin and vimentin. Activated by TβR, ERK promotes the conversion of β-catenin in the nucleus, leading to the increased expression of fibronectin. H₂S promotes Smad7 expression to reduce the combination of TβRII and TβRI, preventing this process. At the same time, H₂S lyses the disulfide bond in the active TGF-β1 dimer, promoting the formation of inactive TGF-β1 monomers. In addition, increases in the expression of matrix-associated proteins are associated with the activation of the IR/IRS-2/Akt-mTORC1/mRNA transcriptional signaling axis. H₂S reduces ROS and collagen cross-linking by regulating MMPs/PARP-1/HIF-1. Hypoxia is associated with methylation and expression silencing of the Klotho promoter. H₂S can significantly improve hypoxia, reverse Klotho promoter methylation and increase Klotho expression. TGF-β1, transforming growth factor-β1; TβR, TGF-β receptor; ERK, extracellular signal-regulated kinase; ROS, reactive oxygen species; H₂S, hydrogen sulfide; IR, insulin receptor; IRS, IR substrate; mTORC, mammalian target of rapamycin complex 1; MMP, matrix metalloproteinase; PARP, poly ADP-ribose-polymerase; HIF-1, hypoxia-inducible factor-1; p-, phosphorylated.