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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/F410    most recent 00145.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sen, U. Articles by Tyagi, S. C. PubMed PubMed Citation Articles by Sen, U. Articles by Tyagi, S. C.

Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky

Submitted 11 March 2009 ; accepted in final form 19 May 2009

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.

cystathionine-β synthase; cystathionine- lyase; homocysteine; matrix metalloproteinase