A Novel Role for Sox6 in Renin Expression Control During Renal Artery Stenosis Induced Hypertension

Abstract

Study ObjectiveWe wanted to determine if the transcription factor Sox6 played a role in renin expression control and in the hypertension induced by renal artery stenosis. In renal artery stenosis, renin is a key disease driver. Renin catalyzes the rate limiting step in the Renin Angiotensin Aldosterone System (RAAS); converting angiotensinogen to angiotensin I. We used a novel transgenic mouse (Ren1dCre/Sox6fl/fl) to determine the impact of specific Sox6 ablation in renin expression during JG cell expansion and renal artery stenosis renal induced hypertension.MethodsIn vivo: JG cell expansion was induced by 10 days of low sodium diet (0.01% Na) and furosemide (0.1 mg/g body weight). Renal artery stenosis was induced by the 2 Kidney 1 clip (2K1C) Goldblatt model; renin is overexpressed in the clipped kidney with renin expression being repressed in contralateral kidney. In vitro: primary renal Mesenchymal Stromal Cells (MSC) were isolated from wild‐type mice. MSC were differentiated into renin expressing cells by 7 days I&F (3‐isobutyl‐methyl‐xanthine (IBMX)‐100 uM and Forskolin‐10 uM) treatment.ResultsI&F induced renin expression in MSCs (Renin relative expression to gapdh 0.0153±0.005, n=3, P= 0.05, no renin expression in control MSCs). In the Ren1dCre/Sox6fl/fl there was no difference in blood pressure or heart rate at base line. However, under conditions that promote JG cell expansion, Sox6 ablation halted the increase in the number of JG cells (8.75 fold decrease, n= 6 to 9, P= 0.001). In our preliminary study we found that specific knock‐out of Sox6 in renin expressing cells protected the kidney against renal artery stenosis injury when compared to control mice (two mice per group). After renal artery stenosis, wild‐type kidneys were one‐third the size of Ren1dCre/Sox6fl/fl kidneys. In addition, renin expression was ~50% higher in the wild‐type group.ConclusionOur data indicates that Sox6 plays a novel role in renal physiology; modulating renin expression during pathological conditions. These results will aid in the discovery of a novel transcriptional regulatory network controlled by Sox6, involved in blood pressure regulation. Identification of this novel pathway and its regulators may lead to new therapies for blood pressure control aiming at decreasing cardiovascular disease in hypertensive patients.Support or Funding InformationResearch was supported by American Heart Association Scientist Development Award to JAG (16SDG29880007), the Vanderbilt University Medical Center Faculty Research Scholars Program, and NHLBI Research Scientist Development Grant 1K01HL135461‐01 to JAGThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.