The Role of Hydrogen Sulfide in Renal System

Abstract

Hydrogen sulfide has gained recognition as the third gaseous signaling molecule after nitric oxide and carbon monoxide. This review surveys the emerging role of H₂S in mammalian renal system, with emphasis on both renal physiology and diseases. H₂S is produced redundantly by four pathways in kidney, indicating the abundance of this gaseous molecule in the organ. In physiological conditions, H₂S was found to regulate the excretory function of the kidney possibly by the inhibitory effect on sodium transporters on renal tubular cells. Likewise, it also influences the release of renin from juxtaglomerular cells and thereby modulates blood pressure. A possible role of H₂S as an oxygen sensor has also been discussed, especially at renal medulla. Alternation of H₂S level has been implicated in various pathological conditions such as renal ischemia/reperfusion, obstructive nephropathy, diabetic nephropathy, and hypertensive nephropathy. Moreover, H₂S donors exhibit broad beneficial effects in renal diseases although a few conflicts need to be resolved. Further research reveals that multiple mechanisms are underlying the protective effects of H₂S, including anti-inflammation, anti-oxidation, and anti-apoptosis. In the review, several research directions are also proposed including the role of mitochondrial H₂S in renal diseases, H₂S delivery to kidney by targeting D-amino acid oxidase/3-mercaptopyruvate sulfurtransferase (DAO/3-MST) pathway, effect of drug-like H₂S donors in kidney diseases and understanding the molecular mechanism of H₂S. The completion of the studies in these directions will not only improves our understanding of renal H₂S functions but may also be critical to translate H₂S to be a new therapy for renal diseases.

Keywords: H2S; acute kidney injury; chronic kidney disease; diabetic nephropathy; hydrogen sulfide; renal physiology.

FIGURE 1

Endogenous synthesis of H₂S by four pathways in renal system. (1) CBS mediated H₂S synthesis by using L-cysteine as the substrate in cytosol; (2) CSE mediated H₂S synthesis with L-cysteine as the substrate in cytosol; (3) CAT transforms L-cysteine into 3MP which is further catalyzed by 3-MST into H₂S in mitochondria; (4) Peroxisome resident DAO catalyzes D-cysteine into 3MP which is then exchanged into mitochondria and utilized by 3-MST for the production of H₂S in mitochondria. CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; 3-MST, 3-mercaptopyruvate sulfurtransferase; CAT, cysteine aminotransferase; DAO, D-amino acid oxidase; 3MP, 3-mercaptopyruvate.

FIGURE 2

Effects of H₂S on renal regulation. (A) H₂S inhibits the activity of tubular NKCC and NKA, thereby enhancing renal excretory function such as GFR, UNa.V and Uk.V. (B) H₂S suppresses renin release by inhibition of AC activity and ROS production in GC cells. (C) H₂S as an O₂ sensor in the kidney. In normoxic condition, H₂S is metabolized into sulfates in the presence of O₂; in hypoxic condition, the shortage of O₂ leads to the accumulation of H₂S which helps to restore O₂ level by enhancing blood flow and suppressing tubular transport activity in kidney. NKCC, Na⁺/K⁺/2Cl^- cotransporter; NKA, Na⁺/K⁺ ATPase; GFR, glomerular filtration rate; UNa⋅V, urinary sodium; Uk⋅V, urinary potassium; β1, β1-adrenoceptor; ROS, reactive oxygen species; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; JG cell, juxtaglomerular cell.

FIGURE 3

Hydrogen sulfide in DN. (A) ROS mediated MMP-9 up-regulation reduces the level of CBS and CSE in DN. (B) Mechanisms underlying the protective effect of H₂S in DN. (1) H₂S inhibits ROS formation by activating Nrf2 pathway; (2) H₂S activates AMPK, thereby suppressing PI3K/Akt/mTORC1 signaling and subsequent protein synthesis; (3) H₂S stimulates NO formation by induction of iNOS expression which inhibits NOX4 level and ROS production. ROS, reactive oxygen species; MMP-9, matrix metalloproteinase-9; AMPK, AMP-activated protein kinase; NO, nitric oxide; iNOS, inducible nitric oxide synthase; mTOR, mechanistic target of rapamycin.