SIRT 1 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 ( SIRT 1), a class III histone deacetylase. Here, we investigated the regulatory role of SIRT 1 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 SIRT 1 or histone acetylase p300 overexpression or knockdown. mRNA expressions of ET ‐1, TGF ‐β1, SIRT 1, p300 and collagen 1α(I) were examined. SIRT 1 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 SIRT 1 overexpressing transgenic mice with or without streptozotocin induced diabetes. Renal functions were evaluated. In the endothelial cells ( EC s), 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 SIRT 1 levels. These changes were rectified in the EC s following p300 silencing or by SIRT 1 overexpression, whereas SIRT 1 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 SIRT 1 overexpressing transgenic mice with diabetes. This study showed a novel SIRT 1 mediated protection against renal and retinal injury in diabetes, regulated through p300, ET ‐1 and TGF ‐β1.