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.

Sox6 expression and aneurysms of the thoracic and abdominal aorta

“…Blood pressure measurement. Blood pressure measurements were performed using a tail-cuff method following previously reported recommendation for precise measurements previously reported 15 . Blood pressure was also measured 4 weeks after Ang II infusion.…”

“…We have previously found that Sox6 has a function as a regulator of renin expression controlling the rate limiting step in RAAS 15,16 . Knocking out Sox6 in Ren1d+ cells inhibited renal artery stenosis induced hypertension and kidney injury 15 .…”

“…We have previously found that Sox6 has a function as a regulator of renin expression controlling the rate limiting step in RAAS 15,16 . Knocking out Sox6 in Ren1d+ cells inhibited renal artery stenosis induced hypertension and kidney injury 15 . Sox6 has previously been reported as a specific regulon of smooth muscle cells in a single cell RNA sequence (RNAseq) study of murine abdominal aortic aneurysm 17 .…”

Renin Angiotensin Aldosterone System Functions in Renovascular Hypertension

“…This stimulation triggers a series of events starting with renin release leading to angiotensin II (Ang II) production, decrease in sodium excretion, increase sympathetic tone; all contributing to the development of hypertension (Figure 1) [17,18]. When there is a need for renin expression and release, the number of renin expressing cells increase a process known as Juxtaglomerular (JG) cell recruitment [19][20][21][22][23][24] involving the trans differentiation of vascular smooth muscle cells into renin expressing cells along the afferent arteriole [20,21,23]. JG cell recruitment is well documented in this model [25][26][27].…”

“…RAS is common in atherosclerotic patients and caused hypertension, oxidative stress, and kidney damage [7,9]. Increased oxidative stress has been reported in humans as well as in two kidney one clip (2K1C) animal model and other hypertensive animal models [24,[55][56][57][58][59][60]. Changes in renal perfusion activate RAAS and increase the sympathetic activity of the afferent renal nerves contributing to renovascular hypertension and end-stage renal disease during RAS [61].…”