Hydrogen sulfide regulates homocysteine-mediated glomerulosclerosis.
OBJECTIVE
In this study we tested the hypothesis that H(2)S regulates collagen deposition, matrix metalloproteinases (MMP) and inflammatory molecules during hyperhomocysteinemia (HHcy) resulting in attenuation of glomerulosclerosis and improved renal function.


METHODS
A genetic model of HHcy, cystathionine beta-synthase heterozygous (CBS+/-) and wild-type (WT) 2-kidney (2K) mice were used in this study and supplemented with or without NaHS (30 micromol/l, H(2)S donor) in drinking water for 8 weeks. To expedite the renal damage associated with HHcy, uninephrectomized (1K) mice of similar groups were also used.


RESULTS
Results demonstrated that NAD(P)H oxidase (p47(phox)subunit) and blood pressure were upregulated in WT 1K, CBS+/- 2K and CBS+/- 1K mice with downregulation of H(2)S production and reduced glomerular filtration rate. These changes were normalized with H(2)S supplementation. Both pro- and active MMP-2 and -9 and collagen protein expressions and glomerular depositions were also upregulated in WT 1K, CBS+/- 2K and CBS+/- 1K mice. Increased expressions of inflammatory molecules, intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1, as well as increased macrophage infiltration, were detected in WT 1K, CBS+/- 2K and CBS+/- 1K mice. These changes were ameliorated with H(2)S supplementation.


CONCLUSIONS
Together, these results suggest that increased oxidative stress and decreased H(2)S in HHcy causes matrix remodeling and inflammation resulting in glomerulosclerosis and reduced renal function.
Sen
Utpal
U
Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA. u0sen001 @ louisville.edu
Munjal
Charu
C
Qipshidze
Natia
N
Abe
Oluwasegun
O
Gargoum
Riyad
R
Tyagi
Suresh C
SC
D000818:Animals; D003094:Collagen / Q000737:chemistry; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D015536:Down-Regulation; D006710:Homocysteine / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000378:metabolism; D007249:Inflammation; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
D006710:Homocysteine; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide
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