Dot1a Functions as a Novel Renoprotective Factor by Repressing Endothelin 1 in Diabetic Mice

Abstract

Our goal is to determine if aldosterone‐downregulated histone H3 K79 methyltransferase Dot1a represses endothelin 1 (ET1) and thus has a renoprotective role in diabetic mice. We used our Dot1lAC mice that lack Dot1l and thus Dot1a specifically in Aqp2+ cells, as the model system. After induction of diabetes with Streptozotocin for three months, diabetic Dot1lAC mice vs. control had more prominent features mimicking human chronic kidney disease (CKD), which was associated with increased ET1 expression. The CKD features include proteinuria, extreme polyuria, natriuresis, interstitial fibrosis, mononuclear cell infiltrate, and various tubular abnormalities (dilated lumen, epithelial thinning, nuclear irregularity, eosinophilic cytoplasm, and severe tubular basement membrane thickening). Administration of ET1 inhibitors ameliorates the kidney injury and function. Therefore, our study for the first time linked aldosterone to kidney injury through Dot1a and ET1, identified a novel role of Dot1a in renal protection possibly by repressing ET1, established diabetic Dot1lAC as a novel mouse model for CKD, and reinforces the notion that blocking ET1 as a potential therapeutic strategy for CKD.