Abstract 475: The Transcription Factor ETS-1: A Critical Mediator of Renal Injury in Salt Sensitive Hypertension

Abstract

The transcription factor ETS-1 regulates the expression of several growth factors, chemokines and cytokines. We have recently shown that ETS-1 is a mediator of the pro-inflammatory and pro-fibrotic effects of Angiotensin II in the kidney (HTN ’12). Herein, we tested the hypothesis that the renal expression of ETS-1 is increased in the Dahl salt-sensitive (DS) rat, a paradigm of salt-sensitive hypertension in humans, and that ETS-1 mediates renal injury in this model of hypertension. DS rats (n=6 per group) were fed a normal salt diet (0.5% NaCl, NS) or a high salt diet (4% NaCl, HS) for 4 weeks. Four additional groups (n=6 per group) on HS diet received: ETS-1 dominant negative peptide (HS/DN, 10mg/kg/day) to block ETS-1, a control ETS-1 mutant peptide (HS/MU, 10mg /kg/day), the AT1 receptor blocker Candesartan (HS/ARB 10 mg/kg/day) or a combination of DN and ARB (HS/DN/ARB). HS rats had a ~ 3 fold increase in the cortical expression of ETS-1 as assessed by western blot (WB). Treatment with DN, MU, ARB or DN/ARB resulted in small and non-significant reductions in BP as compared to HS. (Table). Compared with LS, HS rats had increased proteinuria (Bio-Rad), higher glomerular injury score (GIS), increased fibronectin expression (WB) and urinary TGF-β (ELISA) that were improved by DN but not by MU (table). ARB reduced proteinuria and GIS (table). Treatment with DN/ARB resulted in further improvements in renal injury as compared to DN and ARB (table). In conclusion we have demonstrated that hypertensive DS rats have increased cortical expression of ETS-1 and that blockade of ETS-1 improves renal injury in this model of hypertension.