title: SIRT1 reduction causes renal and retinal injury in diabetes through endothelin 1 and transforming growth factor β1.
abstract: 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.
authors.affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Rokhsana
authors.initials: R
authors.lastname: Mortuza
authors.affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Biao
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Pathology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada.
authors.forename: Subrata
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000419:Albuminuria / Q000097:blood / Q000150:complications; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019332:Endothelin-1 / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D056564:Sirtuin 1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
chemical_list: D024042:Collagen Type I; D019332:Endothelin-1; D005353:Fibronectins; D005947:Glucose; D056564:Sirtuin 1; D053773:Transforming Growth Factor beta1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: ET-1; SIRT1; TGF-β1; endothelial cells; p300