Abstract
The accumulation of homocysteine (Hcy) during chronic kidney failure (CKD) can exert toxic effects on the glomeruli and tubulo-interstitial region. Among the potential mechanisms, the formation of highly reactive metabolite, Hcy thiolactone, is known to modify proteins by N-homocysteinylation, leading to protein degradation, stress and impaired function. Previous studies documented impaired nitric oxide production and altered caveolin expression in hyperhomocysteinemia (HHcy), leading to endothelial dysfunction. The aim of this study was to determine whether Hhcy homocysteinylates endothelial nitric oxide synthase (eNOS) and alters caveolin-1 expression to decrease nitric oxide bioavailability, causing hypertension and renal dysfunction. We also examined whether hydrogen sulfide (H2S) could dehomocysteinylate eNOS to protect the kidney. WT and Cystathionine β-Synthase deficient (CBS+/−) mice representing HHcy were treated without or with sodium hydrogen sulfide (NaHS), a H2S donor (30 µM), in drinking water for 8 weeks. Hhcy mice (CBS+/−) showed low levels of plasma H2S, elevated systolic blood pressure (SBP) and renal dysfunction. H2S treatment reduced SBP and improved renal function. Hhcy was associated with homocysteinylation of eNOS, reduced enzyme activity and upregulation of caveolin-1 expression. Further, Hhcy increased extracellular matrix (ECM) protein deposition and disruption of gap junction proteins, connexins. H2S treatment reversed the changes above and transfection of triple genes producing H2S (CBS, CSE and 3MST) showed reduction of vascular smooth muscle cell proliferation. We conclude that during Hhcy, homocysteinylation of eNOS and disruption of caveolin-mediated regulation leads to ECM remodeling and hypertension, and H2S treatment attenuates renovascular damage.
Highlights
In the body, homocysteine is metabolized mainly by the enzymes, cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase (CBS, CSE and 3-MST respectively)
The aim of the present study was to investigate whether homocysteinylation of endothelial nitric oxide synthase (eNOS) and disruption of caveolin-mediated eNOS regulation leads to hypertension and renal dysfunction
We investigated whether H2S supplementation dehomocysteinylates eNOS and reduces vascular smooth muscle cell proliferation and extracellular matrix protein deposition to protect the kidney from Hhcy mediated injury
Summary
Homocysteine is metabolized mainly by the enzymes, cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase (CBS, CSE and 3-MST respectively). Some of the beneficial effects of H2S are attributed to the activation of KATP (ATP-sensitive K+) channels or scavenging free radicals[19]. It has been speculated whether H2S is involved in posttranslational protein modification for some of its biological effects[20]. We investigated whether H2S supplementation dehomocysteinylates eNOS and reduces vascular smooth muscle cell proliferation and extracellular matrix protein deposition to protect the kidney from Hhcy mediated injury
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