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.

SIRT1 rs10823108 and FOXO1 rs17446614 responsible for genetic susceptibility to diabetic nephropathy

“…The effects of SIRT1 polymorphisms on susceptibility to DN might be mediated by differences in the metabolic state among individuals, including glycemic control, obesity, blood pressure, respectively 25 – 27 . The evidence in Wild-type (C57BL/6 J) and SIRT1 transgenic mice (C57BL/6-Actb tm3.1(Sirt1)Npa /J) showed SIRT1 mediated protection against renal and retinal injury in DN 28 . FOXO1, as an important target for insulin and growth factor signaling, has been reported to play key roles in regulating metabolism, cell proliferation, cell cycle, apoptosis and oxidative stress response by regulating the expression of functionally important target genes 29 , 30 .…”

Endothelin-1 Regulation Is Entangled in a Complex Web of Epigenetic Mechanisms in Diabetes

“…Although chronic hyperglycemic environments can facilitate chromatin remodeling by histone methylation, histone acetylation can also significantly contribute to chromatin state dynamics. Former studies from our laboratory have indicated that the upregulation of histone acetyltransferase p300 can cause increased EDN1 promoter activity (Chen et al 2009), reduced expression of the class II histone deacetylase SIRT1 (Mortuza et al 2015), and increased expressions of ET-1 transcripts, extracellular matrix (ECM) proteins and vasoactive factors (Chen et al 2009. Collectively, our past and current findings demonstrate that pathologies like diabetes can cause unique alterations in histone modification patterns, which may ultimately enhance EDN1 transcriptional activity and contribute to elevated ET-1 protein levels.…”

MALAT1: A regulator of inflammatory cytokines in diabetic complications

“…At the transcriptional level, regulating the production of downstream transcriptional factors is a major mechanism in the genesis of downstream effects . We have previously shown that alterations in epigenetic modifications such as histone acetylation and specific microRNAs (miRs) can affect this transcriptional regulation and mediate glucose‐induced abnormalities . Nevertheless, the transcriptional process can also be controlled by long noncoding RNAs (lncRNAs) …”