Abstract
The molecular mechanism linking aldosterone and endothelin-1 in the development of diabetic nephropathy has not been completely elucidated. Here, we provide evidence showing that streptozotocin-induced diabetic rats have significantly increased aldosterone and endothelin-1 in the kidney tissue and markedly decreased expression of Dot1a and Af9. Blocking aldosterone with spironolactone significantly reduced proteinuria, glomerulosclerosis, tubulointerstitial injury and endothelin-1 expression, and significantly increased Dot1a and Af9 expression. Increasing Dot1a and Af9 expression by spironolactone or by stable transfection led to impaired endothelin-1 expression in NRK-52 cells. In contrast, downregulation of Dot1a and Af9 by aldosterone in NRK-52E cells caused upregulation of endothelin-1. Genetic inactivation of Dot1l, which encodes Dot1a, in Aqp2-expressing principal cells of mouse kidney impaired association of Dot1a and H3 dimethyl K79 with the specific subregions of endothelin-1 promoter, and upregulates endothelin-1 mRNA and protein expression. Our data suggest that Dot1a and Af9 repress endothelin-1 in vitro and in vivo. Excessive aldosterone induces kidney injury, in part possibly by downregulating Dot1a and Af9, and thus relieving Dot1a-Af9-mediated repression to increase endothelin-1 transcription. Spironolactone ameliorates kidney injury in Streptozotocin-induced diabetic rats, possibly by restoring Dot1a-Af9-mediated repression to reduce endothelin-1 expression. Therefore, Dot1a and Af9 as aldosterone-downregulated targets are negative regulators of endothelin-1 transcription in vitro and in vivo, and may be considered as new potential therapeutic targets of kidney injury in diabetes.
Highlights
An excessively stimulated renin-angiotensin-aldosterone system has been demonstrated to play a central role in the pathogenesis of diabetic nephropathy (DN)
We have developed a new Dot1l conditional knockout mouse model (Dot1lAC), which lacks the vast majority, if not all, of Dot1a function including the methyltransferase activity and the ability to interact with Af9 in Aqp2-expressing renal principal cells (Wu et al, 2011 ASN abstract 21278, and Wu et al, 2011 ASN abstract 20636)
We describe the following new findings: 1) The increased aldosterone and ET-1 synthesis in the diabetic kidney tissue are associated with decreased expression of Dot1a and Af9; Figure 11
Summary
An excessively stimulated renin-angiotensin-aldosterone system has been demonstrated to play a central role in the pathogenesis of diabetic nephropathy (DN). Application of drugs blocking this system is one of the most effective interventions for DN [1]. These inhibitors elicit anti-inflammatory, anti-proliferative and anti-oxidative effects [2]. Spironolactone, a nonselective aldosterone blocker, produces beneficial effects in multiple animal models of renal injury induced by unilateral ureteral obstruction [3], cyclosporin nephrotoxicity [4], hypertension [5] and streptozotocin [6]. Clinical trials suggest that addition of spironolactone to an angiotensin-converting enzyme inhibitor may further improve proteinuria in patients with DN [7].
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