Abstract 15751: A New Role of Sox6 in Renin Regulation

Abstract

Introduction: The renin-angiotensin system (RAS) is an important component of blood pressure regulation in mammals. Renin catalyzes the rate limiting step of RAS, is produced and stored by Juxtaglomerular (JG) cells in the kidney. However, the transcriptional mechanisms that govern the specification of renin expressing cells under normal or pathophysiological conditions remain poorly understood. During blood pressure changes the number of adult renal cells expressing renin increase through a process termed JG recruitment. We found that this process involves differentiation mesenchymal stromal-like cells (MSC) to renin expressing cells. Our aim in this study was to determine new regulators of renin cell fate during kidney development and JG recruitment. Methods: Gene expression profiles of MSC and JG cells were performed with Affymetrix Mouse 430 2.0 array. In vitro assays were performed in adult renal MSCs isolated from C57BL6 Ren1c YFP mice. Renin expression in vitro was induced by treatment with IBMX and Forskolin. MSC were transduced with lentivirus carrying vectors for Sox6, Sox6 shRNA or controls. Ex vivo analysis was performed in embryonic kidneys (14.5 dpc) isolated and transduced with Sox6 or scrambled shRNA, kidneys were then cultured for 4 days and the expression of Sox6 and Renin analyzed by IHC. Results: Data showed that the transcription factor Sox6 is expressed in renin producing cells in the developing kidney (n=4) and in the adult kidney after stimulation that promotes JG recruitment (n=3). Overexpression of Sox6 (n=3, P<0.05) enhanced differentiation of renal MSCs to renin producing cells in vitro , and Sox6 knockdown reduced differentiation of renal MSC to renin producing cells in vitro (6-fold, n=4, P<0.01). Furthermore, knockdown of Sox6 in an ex vivo model of kidney development resulted in a 5-fold reduction in renin expressing cells (n=4, P<0.05). Conclusion: These results support a novel role for Sox6 in the development of renin expressing cells. This may have implications for renal development and physiology, opening new possibilities of addressing questions regarding both developmental and physiological regulation of renin.