Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure

Abstract

Elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), is associated with end-stage renal diseases. Hcy metabolizes in the body to produce hydrogen sulfide (H2S), and studies have demonstrated a protective role of H2S in end-stage organ failure. However, the role of H2S in HHcy-associated renal diseases is unclear. The present study was aimed to determine the role of H2S in HHcy-associated renal damage. Cystathionine-β-synthase heterozygous (CBS+/−) and wild-type (WT, C57BL/6J) mice with two kidney (2-K) were used in this study and supplemented with or without NaHS (30 μmol/l, H2S donor) in the drinking water. To expedite the HHcy-associated glomerular damage, uninephrectomized (1-K) CBS(+/−) and 1-K WT mice were also used with or without NaHS supplementation. Plasma Hcy levels were elevated in CBS(+/−) 2-K and 1-K and WT 1-K mice along with increased proteinuria, whereas, plasma levels of H2S were attenuated in these groups compared with WT 2-K mice. Interestingly, H2S supplementation increased plasma H2S level and normalized the urinary protein secretion in the similar groups of animals as above. Increased activity of matrix metalloproteinase (MMP)-2 and -9 and apoptotic cells were observed in the renal cortical tissues of CBS(+/−) 2-K and 1-K and WT 1-K mice; however, H2S prevented apoptotic cell death and normalized increased MMP activities. Increased expression of desmin and downregulation of nephrin in the cortical tissue of CBS(+/−) 2-K and 1-K and WT 1-K mice were ameliorated with H2S supplementation. Additionally, in the kidney tissues of CBS(+/−) 2-K and 1-K and WT 1-K mice, increased superoxide (O2•−) production and reduced glutathione (GSH)-to-oxidized glutathione (GSSG) ratio were normalized with exogenous H2S supplementation. These results demonstrate that HHcy-associated renal damage is related to decreased endogenous H2S generation in the body. Additionally, here we demonstrate with evidence that H2S supplementation prevents HHcy-associated renal damage, in part, through its antioxidant properties.