SIRT1 reduction causes renal and retinal injury in diabetes through endothelin 1 and transforming growth factor β1.
In diabetes, hyperglycaemia causes up-regulation of endothelin 1 (ET-1) and transforming growth factor beta 1 (TGF-β1). Previously we showed glucose reduces sirtuin1 (SIRT1), a class III histone deacetylase. Here, we investigated the regulatory role of SIRT1 on ET-1 and TGF-β1 expression. Human microvascular endothelial cells were examined following incubation with 25 mmol/l glucose (HG) and 5 mmol/l glucose (NG) with or without SIRT1 or histone acetylase p300 overexpression or knockdown. mRNA expressions of ET-1, TGF-β1, SIRT1, p300 and collagen 1α(I) were examined. SIRT1 enzyme activity, ET-1 and TGF-β1 protein levels were measured. Histone acetylation and endothelial permeability were further investigated. Similar analyses were performed in the kidneys and retinas of SIRT1 overexpressing transgenic mice with or without streptozotocin induced diabetes. Renal functions were evaluated. In the endothelial cells (ECs), HG caused increased permeability and escalated production of ET-1, TGF-β1, collagen Iα(I). These cells also showed increased p300 expression, histone acetylation and reduced SIRT1 levels. These changes were rectified in the ECs following p300 silencing or by SIRT1 overexpression, whereas SIRT1 knockdown or p300 overexpression in NG mimicked the effects of HG. High ET-1 and TGF-β1 levels were seen in the kidneys and retinas of diabetic mice along with micro-albuminuria and increased fibronectin protein (marker of glucose-induced cell injury) levels. Interestingly, these detrimental changes were blunted in SIRT1 overexpressing transgenic mice with diabetes. This study showed a novel SIRT1 mediated protection against renal and retinal injury in diabetes, regulated through p300, ET-1 and TGF-β1.
['Mortuza|Rokhsana|R|', 'Feng|Biao|B|', 'Chakrabarti|Subrata|S|']
D000419:Albuminuria D000818:Animals D002463:Cell Membrane Permeability D024042:Collagen Type I D003921:Diabetes Mellitus, Experimental D042783:Endothelial Cells D019332:Endothelin-1 D005353:Fibronectins D005947:Glucose D057809:HEK293 Cells D006801:Humans D007668:Kidney D007677:Kidney Function Tests D008297:Male D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D055806:Microvessels D018384:Oxidative Stress D060888:Real-Time Polymerase Chain Reaction D012160:Retina D056564:Sirtuin 1 D053773:Transforming Growth Factor beta1 D015854:Up-Regulation D050880:p300-CBP Transcription Factors
SIRT1 ET-1 TGF-β1 endothelial cells p300