Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure.
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 (H(2)S), and studies have demonstrated a protective role of H(2)S in end-stage organ failure. However, the role of H(2)S in HHcy-associated renal diseases is unclear. The present study was aimed to determine the role of H(2)S in HHcy-associated renal damage. Cystathionine-beta-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 micromol/l, H(2)S 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 H(2)S were attenuated in these groups compared with WT 2-K mice. Interestingly, H(2)S supplementation increased plasma H(2)S 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, H(2)S 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 H(2)S supplementation. Additionally, in the kidney tissues of CBS(+/-) 2-K and 1-K and WT 1-K mice, increased superoxide (O(2)(*-)) production and reduced glutathione (GSH)-to-oxidized glutathione (GSSG) ratio were normalized with exogenous H(2)S supplementation. These results demonstrate that HHcy-associated renal damage is related to decreased endogenous H(2)S generation in the body. Additionally, here we demonstrate with evidence that H(2)S supplementation prevents HHcy-associated renal damage, in part, through its antioxidant properties.
Sen
Utpal
U
Dept. of Physiology & Biophysics, Univ. of Louisville School of Medicine, 500 S. Preston St., Louisville, KY 40202, USA. u0sen001@louisville.edu
Basu
Poulami
P
Abe
Oluwasegun A
OA
Givvimani
Srikanth
S
Tyagi
Neetu
N
Metreveli
Naira
N
Shah
Karan S
KS
Passmore
John C
JC
Tyagi
Suresh C
SC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006710:Homocysteine / Q000097:blood; D006862:Hydrogen Sulfide / Q000097:blood / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects; D011507:Proteinuria / Q000378:metabolism / Q000517:prevention & control; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D003893:Desmin; D008565:Membrane Proteins; D013440:Sulfides; C113267:nephrin; D006710:Homocysteine; D013481:Superoxides; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D003541:Cystathionine beta-Synthase; C025451:sodium bisulfide; D005978:Glutathione; D019803:Glutathione Disulfide; D006862:Hydrogen Sulfide