Diabetic retinopathy and transcriptional regulation of a small molecular weight G-Protein, Rac1.
In diabetic retinopathy, increased cytosolic reactive oxygen species, produced by NADPH oxidase (Nox), damage mitochondria, and this accelerates apoptosis of retinal capillary cells, resulting in the histopathology. Activation of Nox2 is mediated by a small molecular weight GTPase, Rac1, and retinal Rac1 is activated in diabetes. Our goal is to investigate the molecular mechanism responsible for transcriptional activation of Rac1 in the development of diabetic retinopathy. Using retinal microvessels, the site of histopathology associated with diabetic retinopathy, from streptozotocin-induced diabetic rats, we investigated the binding of the nuclear transcriptional factor-kB (NF-kB) at Rac1 promoter. Since activation of NF-kB is regulated by its acetylation-deacetylation, the role of acetylation in Rac1 transcription was confirmed in the retina from diabetic mice overexpressing a deacetylase, Sirtuin 1. Diabetes increased the binding of p65 subunit of NF-kB at the Rac1 promoter. Overexpression of Sirtuin 1 prevented hyper-acetylation of p65, decreased its binding at the Rac1 promoter and ameliorated Rac1-Nox2 mediated mitochondrial damage. Thus, in diabetes Rac1 transcriptional activation in the retina is mediated by acetylation of NF-kB, and modulation of acetylation during the early stages of diabetic retinopathy has potential to inhibit/retard its development.
['Kowluru|Renu A|RA|', 'Mishra|Manish|M|', 'Kumar|Binit|B|']
D000704:Analysis of Variance D000818:Animals D004249:DNA Damage D003921:Diabetes Mellitus, Experimental D003930:Diabetic Retinopathy D020869:Gene Expression Profiling D008297:Male D055806:Microvessels D008928:Mitochondria D019255:NADPH Oxidases D016328:NF-kappa B D051381:Rats D017208:Rats, Wistar D012171:Retinal Vessels D056564:Sirtuin 1 D014158:Transcription, Genetic D020830:rac1 GTP-Binding Protein
Diabetic retinopathy Transcriptional regulation Rac1 Acetylation Sirtuin 1