Abstract MP08: New Function Of Sox6 In Renovascular Hypertension Induced Oxidative Stress And Kidney Damage Through Renin, Prorenin And The (pro)renin Receptor Expression Control.

Abstract

Introduction: During renovascular hypertension induced by renal artery stenosis (RAStenosis), smooth muscle cells are recruited to produce and release renin compensating for the decrease in renal perfusion. In renovascular hypertension, renin expression increases causing a surge in angiotensin II, oxidative stress and kidney damage. Here we present a new function of the transcription factor Sox6 in kidney injury and oxidative damage during RAStenosis. Methods: We used a mouse model in which Sox6 is knockout specifically in renin expressing cells (Ren1d Cre /Sox6 fl/fl -Sox6-KO). We developed a modified 2-kidney 1-clip (2K1C) Goldblatt model to induce RAStenosis. We measured superoxide production (pmol/mg pr) in kidney using high-performance liquid chromatography in Sox6-KO and Ren1d Cre /Sox6 wt/wt (Sox6-WT) littermates. Renin, prorenin, (pro)renin receptor (PRR) and N-GAL expressions were measured using Western blot using β-actin as housekeeping gene. Western blot band density analysis was performed using ImageJ. Kidney injury was determined by measuring creatinine clearance. Results: We found that Sox6-KO mice exhibit lower expression of renin (0.36 vs. 0.45, SEM= 0.11 n= 11-15, p<0.01), and prorenin (1.25 vs. 2.07, SEM=0.30, n=11-15, p<0.05) and mice are protected against renovascular hypertension (SBP, 114.5 vs. 131.1, SEM=5.31 n=13-15, p<0.01), and kidney injury measuring N-GAL expression (1.3 vs. 2.7, SEM=0.38, n=6-8, p<0.01) and creatinine clearance (2372 vs. 1341, SEM=342.3, n=4-5, p<0.05). Furthermore, we found that the levels of superoxide were significantly lower in Sox6-KO mice compared to Sox6-WT littermates (218 vs 47, SEM=50.6, N=7, P<0.01). The expression of PRR was significantly lower in Sox6-KO compared to Sox6-WT during RAStenosis (1.23 vs. 0.72, SEM=0.33, n=2-5, p<0.01). Conclusions: Our results show that Sox6 depletion in renin expressing cells inhibits the increase in renovascular hypertension and prevents the increase in renin, prorenin, PRR, and N-GAL expression as well as superoxide production, preserving creatinine clearance during RAStenosis. These results suggest that Sox6 has a new function in hypertension and kidney injury induced by RAS.