Homocysteine Disrupts Balance between MMP-9 and Its Tissue Inhibitor in Diabetic Retinopathy: The Role of DNA Methylation

International Journal of Molecular Sciences
Ghulam Mohammad, Renu A Kowluru

Abstract

High homocysteine is routinely observed in diabetic patients, and this non-protein amino acid is considered as an independent risk factor for diabetic retinopathy. Homocysteine biosynthesis from methionine forms S-adenosyl methionine (SAM), which is a major methyl donor critical in DNA methylation. Hyperhomocysteinemia is implicated in increased oxidative stress and activation of MMP-9, and in diabetic retinopathy, the activation of MMP-9 facilitates capillary cell apoptosis. Our aim was to investigate the mechanism by which homocysteine activates MMP-9 in diabetic retinopathy. Human retinal endothelial cells, incubated with/without 100 μM homocysteine, were analyzed for MMP-9 and its tissue inhibitor Timp1 expressions and interactions, and ROS levels. Timp1 and MMP-9 promoters were analyzed for methylated and hydroxymethylated cytosine levels (5mC and 5hmC respectively) by the DNA capture method, and DNA- methylating (Dnmt1) and hydroxymethylating enzymes (Tet2) binding by chromatin immunoprecipitation. The results were confirmed in retinal microvessels from diabetic rats receiving homocysteine. Homocysteine supplementation exacerbated hyperglycaemia-induced MMP-9 and ROS levels and decreased Timp1 and its interactions with MM...Continue Reading

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Citations

May 28, 2020·American Journal of Physiology. Cell Physiology·Erfan Aref-EshghiSubrata Chakrabarti
Sep 24, 2020·Journal of Clinical Medicine·Renu A Kowluru
Dec 30, 2020·Investigative Ophthalmology & Visual Science·Ghulam MohammadRenu A Kowluru
Jul 3, 2021·International Journal of Molecular Sciences·Amany TawfikPragya Rajpurohit

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Methods Mentioned

BETA
ELISA
PCR
Assay
Co-immunoprecipitation
Immunoprecipitation
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