Hydrogen Sulfide Regulates Homocysteine-Mediated Glomerulosclerosis

Abstract

Background/Aims: In this study we tested the hypothesis that H₂S regulates collagen deposition, matrix metalloproteinases (MMP) and inflammatory molecules during hyperhomocysteinemia (HHcy) resulting in attenuation of glomerulosclerosis and improved renal function. Materials and Methods: A genetic model of HHcy, cystathionine β-synthase heterozygous (CBS+/–) and wild-type (WT) 2-kidney (2K) mice were used in this study and supplemented with or without NaHS (30 µmol/l, H₂S 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^phoxsubunit) and blood pressure were upregulated in WT 1K, CBS+/– 2K and CBS+/– 1K mice with downregulation of H₂S production and reduced glomerular filtration rate. These changes were normalized with H₂S 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 H₂S supplementation. Conclusion: Together, these results suggest that increased oxidative stress and decreased H₂S in HHcy causes matrix remodeling and inflammation resulting in glomerulosclerosis and reduced renal function.

Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9

“…Taken together, these results suggest that H 2 S supplementation does not regulate MMP-9, at least, in the present experimental condition. This is in contrast to our previous in vivo findings that H 2 S regulated MMP-9 in one kidney hypertension model (30,31). We expected a similar result in the present study, but the contrast may be due to in vivo vs. in vitro and hypertension vs. hyperglycemic models and remains to be elucidated.…”

Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells

“…Reduction in ischemiareperfusion-induced injury to the kidney has been reported by augmenting cystathionine ␥-lyase expression in the kidney (59). Sen et al (60,61) have also described ameliorative effects of hydrogen sulfide on the progression of kidney disease in rodents with hyperhomocysteinemia. Hydrogen sulfide affords protection to the heart against ischemia-reperfusion injury (5,62), and clinical trials evaluating its therapeutic role in amelioration of ischemic heart disease are underway (44).…”

“…Hydrogen sulfide affords protection to the heart against ischemia-reperfusion injury (5,62), and clinical trials evaluating its therapeutic role in amelioration of ischemic heart disease are underway (44). The mechanisms of cardiac protection may involve diverse pathways and include inhibition of macrophage infiltration of the myocardium, reduction in mitochondrial respiration and preservation of mitochondrial structure, and inhibition of apoptosis (5,61). These protective phenotypes were reproduced by myocardium-specific overexpression of cystathionine ␥-lyase (5).…”

Cystathionine γ-Lyase Protects against Renal Ischemia/Reperfusion by Modulating Oxidative Stress

“…4 Accordingly, CSE-deficient mice (CSE 2/2 ) develop hypertension, 3 analogous to mice lacking endothelial nitric oxide synthase 5 and CBS +/2 mice. 6 In addition, endogenously produced H 2 S is involved in cellular proliferation, 7 angiogenesis, 8 inflammation 9,10 and regulation of protein activity through S-sulfhydration. [11][12][13] Exogenous treatment with H 2 S can induce a reversible hypometabolic, hibernation-like state.…”