Abstract
Introduction: the renin-angiotensin system (RAS) is an important component of blood pressure regulation in mammals. Renin, primarily expressed and secreted by kidney Juxtaglomerular (JG) cells, catalyzes the rate limiting step in RAS. However, the transcriptional mechanisms that govern the specification of renin expressing cells in development and under normal or pathophysiological conditions remain poorly understood. We sought to determine new regulators of renin cell fate during kidney development and JG recruitment. Methods: Gene expression profiles of renal MSC and JG cells were determined by Affymetrix Mouse 430 2.0 array. JG cells and renal MSC were isolated from adult C57Bl6 Ren1c YFP mice by collagenase digestion of the kidney, followed by flow cytometry to select for the cells. Renin expression in vitro was induced by treatment with IBMX and Forskolin. Renal MSCs 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 shRNA or scrambled shRNA. The kidneys were then cultured for 4 days. Results: Microarray data showed that the transcription factor Sox6 was highly expressed in FACS isolated JG cells compared to renal MSC (96-fold, n=3, P<0.05). This finding was validated by qPCR (100-fold, n=4, P<0.05). Sox6 was expressed in renin producing cells during kidney embryogenesis as determined by immunofluorescence and confocal microscopy (E14.5, N=4). Knockdown of Sox6 by shRNA in an ex vivo model of kidney development resulted in a 70% reduction of renin expression (N=4, P<0.01). Differentiation of adult renal MSCs to renin producing cells in vitro was enhanced by overexpression of Sox6 (20-fold, N=6, P<0.01). Knockdown of Sox6 by shRNA inhibited in vitro MSC differentiation (5-fold, N=6, P<0.001). In vivo, low salt and furosemide, which stimulates JG recruitment, increased Sox6 expression (5-fold, N=5, P<0.001) and colocalization with renin. Conclusion: Our results support a novel and critical role for the transcription factor Sox6 in renin cell fate and in renal development and physiology. Further studies can provide an in-depth understanding of the role of Sox 6 in hypertension and its therapy.
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