GYY4137 Mitigates Caveolin‐dependent Renal Remodeling in Hyperhomocysteinemia

Abstract

IntroductionHyperhomocysteinemia (HHcy), an increase in plasma homocysteine levels induces collagen deposition by causing imbalance between MMPs and TIMPs leading to fibrosis, and predisposing hypertension. HHcy also decreases the endogenous production of hydrogen sulfide (H2S) and homocysteinylates endothelial nitric‐oxide synthase (eNOS) resulting in further increase of vascular resistance. In the contrary, deletion of a membrane protein Caveolin‐1 (Cav‐1) is known to mitigate hypertension. However, the interplay between Caveolin, eNOS and MMPs/TIMPs and the role of H2S in HHcy associated renovascular remodeling and hypertension remains largely unknown. We tested the hypothesis that GYY4137, a H2S donor mitigates hyperhomocysteinemic effect in renal microvasculature and thus normalizes vascular tone.MethodsB6.Cg‐Cav1(Cav‐1) mice representing caveolae protein 1 knock‐out and C57BL6/J (WT) mice were treated without or with GYY4137 (0.5 mg/Kg/d, IP) and supplemented without or with Hcy (2% in diet) for a period of 8 weeks.ResultsHHcy decreased plasma H2S levels, upregulated Cav1 and decreased eNOS activity in kidney. HHcy resulted in the upregulation of mRNA and protein levels of matrix metalloproteinases (MMPs) ‐2,‐9,‐1,‐8,‐13 and decreased the activities of tissue inhibitor of metalloproteinases (TIMPs) ‐1,‐2,‐3,‐4. Immunohistochemistry showed increased collagen IV deposition in the glomerular and interstitial areas. GYY4137 treatment reversed these changes in HHcy. In conclusion, our data suggests that H2S mitigates renovascular remodeling by modulating Cav‐1, eNOS and MMPs/TIMPs in HHcy.Support or Funding InformationThis study was supported by National Institute of Health Grant ‐ DK104653 (to U.S.)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.