The transcription factor Sox6 controls renin expression during renal artery stenosis

Abstract

Background: Renal artery stenosis (RAStenosis) or renal artery occlusion is an intractable problem affecting about 6% of people over 65 and up to 40% of the people with coronary or peripheral vascular disease in the Unites States. In RAStenosis, the renal renin angiotensin aldosterone system (RAAS) plays a key role, with renin recognized as the disease driver. Renin is mainly produced in the kidney and in this study, we will determine a new function for the transcription factor Sox6 in the control of renal renin during RAStenosis. Method: We hypothesize that knocking out Sox6 in Ren1d positive cells will protect mice against renovascular hypertension, and kidney injury. To test our hypothesis, we used a new transgenic mouse model the Ren1dcre/Sox6fl/fl (Sox6 KO). In this mouse, Sox6 is knockout in renin expressing cells. We used a modified two kidney one clip (2K1C) Goldblatt mouse model to induce RAStenosis and renovascular hypertension. Blood pressure was measured with tail-cuff method. Renin, prorenin, Sox6, and N-GAL expressions levels were measured with Western blot, in situ hybridization, and immunohistochemistry. Creatinine levels were measured with colorimetric assay. Results: Systolic blood pressure was significantly lower in Sox6 KO two weeks after RAStenosis compared to Sox6 WT (Ren1dcre/Sox6wt/wt). When stenosed kidneys were compared, renin, prorenin, and N-GAL expressions levels in the kidney were lower in Sox6 KO compared to Sox6 WT mice. Furthermore, creatinine clearance was preserved in Sox6 KO compared to Sox6 WT mice. Conclusions: Our data indicate that Sox6 controls renal renin and prorenin expression and as such has a new function in renovascular hypertension induced by RAStenosis. These results point to a novel transcriptional regulatory network controlled by Sox6.