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GYY4137 Modulates Renal Remodeling in Hyperhomocysteinemia
Author(s) -
John AM Sashi Papu,
Sen Utpal
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.570.3
Subject(s) - endocrinology , medicine , hyperhomocysteinemia , enos , matrix metalloproteinase , homocysteine , chemistry , kidney , caveolin 1 , nitric oxide , extracellular matrix , downregulation and upregulation , endothelial nos , nitric oxide synthase , biology , biochemistry , gene
Elevated plasma levels of homocysteine, also known as hyperhomocysteinemia (HHcy), is associated with chronic kidney disease and end‐stage renal failure. HHcy is also a vascular risk factor that causes glomerular remodeling by inducing and accumulating extracellular matrix (ECM) in the glomerular and peri‐glomerular spaces. This remodeling is, in part, due to Hcy‐mediated imbalance between matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) and disruption of cell‐to‐cell gap junction protein, connexins (Cxs). HHcy also contribute to renal microvascular impairment and vasoconstriction due to decreased endogenous hydrogen sulfide (H2S) production and homocysteinylation of endothelial nitric‐oxide synthase (eNOS). However, the molecular events targeting Caveolin, eNOS, MMPs/TIMPs, Cxs and the role of H2S in HHcy associated ECM turnover and renovascular remodeling remain elusive. Hypothesis We investigated whether GYY4137, slow releasing H2S donor ameliorates HHcy effect and renal remodeling. Methods Caveolin protein 1 knockout B6.Cg‐Cav1 (Cav1−/ −), C57BL6/J (WT) and hyperhomocysteinemic CBS+/− mice were supplemented without or with Hcy (2% in diet) and treated without or with GYY4137 (0.5 mg/Kg/d, IP) for a period of 8 weeks. Results HHcy decreased plasma H2S levels, upregulated Cav1 and decreased eNOS activity in the kidney. HHcy also resulted in the upregulation of mRNA and protein levels of MMPs −1, 2, −9, −8, −13 as well as connexins – 40 and −43 and decreased the activities of (TIMPs) −1, −2, −3, −4. Immunohistochemistry results indicated increased collagen IV deposition and expression of connexins in the glomerular and interstitial areas. GYY4137 treatment mitigated these changes in HHcy. In conclusion , our data suggests that H2S alleviates renovascular remodeling by modulating Cav‐1, eNOS, MMPs/TIMPs and Cxs in HHcy. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .