Introduction: Sox6 is a transcription factor known to be important for specification of different cell lineages, and important during embryonic development in vertebrates. Our group recently found that Sox6 plays a new function in renin expression control. Renin is an enzyme that controls the rate limiting step in the Renin Angiotensin Aldosterone System, a key regulator of blood pressure and thus hypertension. Here we report new findings in a novel transgenic mouse in which Sox6 is specifically knocked out in Renin expressing cells (Ren1d Cre /Sox6 fl/fl -Sox6 KO). Methods: Sox6 KO was used to determine the impact of Sox6 ablation in renin expressing cells on renin expression. Blood pressure and heart rate variability were measured by telemetry. Vascular reactivity was measured by wire myography and sympathetic nervous system renal input was determined by renal catecholamines assay. Results: We found that the specific Sox6 ablation in renin expressing cells produced a significant decrease in renin expression at a protein (40% fold decrease, n=7, P=0.01) and mRNA level (37 % fold decrease, n=4, P=0.01) compared to wild type mice. Our data indicates that Sox6 KO has no significant change in baseline blood pressure. However, there is a decrease in heart rate variability in Sox6 KO mice compared to wild type, indicating a dysregulation in the sympathetic and parasympathetic nervous systems (3.22±0.19 vs 1.14±0.32 LF/HF, n=10-13, P<0.05). Regarding vascular function, Sox6 KO mice have an enhanced sensitivity to vasodilators compared to wild type mice which may compensate for the decrease in renin expression (difference in response to sodium nitroprusside was found between 3 nM and 30 nM, n=3-11, P<0.05) and no difference in Acetylcholine response at any concentration. Furthermore, preliminary data indicates that there are no detectable differences in renal norepinephrine concentration between Sox6 KO and wild type mice. Conclusion: Our data indicate that Sox6 has a new function in renin-expressing cells that modulate blood pressure, heart rate variability, and vascular reactivity. Currently we are studying changes in the expression of vascular tone genes in endothelial and smooth muscle cells and changes in the sympathetic tone in the kidney and vascular system.
Introduction: The Renin angiotensin aldosterone system (RAAS) is implicated in renal artery stenosis (RAS) and renovascular hypertension. RAS 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 United States. Renin being the rate limiting enzyme in RAAS is considered the key driver of RAS. The mechanism of renin regulation during RAS is still elusive and warrants further investigation. Here we studied the function of the transcription factor Sox6 in the renin regulation using a new knockout mouse model during RAS. Methods: We used a mouse model in which Sox6 is knockout specifically in renin expressing cells (Sox6 KO). Using these mice, we developed a modified 2-kidney 1-clip (2K1C) Goldblatt model to constrict right renal artery to induce RAS. Two weeks after surgery, renin, prorenin, prorenin receptor (PRR), and N-GAL expressions were measured using Western blot. Blood pressure was measured using tail-cuff method. Creatinine clearance was measured in urine using a colorimetric assay. Results: Comparing Sox6 KO with the Sox6 wild type littermates, we found that Sox6 KO mice exhibit lower expression of renin (0.36 vs. 0.45, SEM= 0.11 n= 11-15, P<0.01) and prorenin (1.25 vs. 2.07, SEM=0.30, n=11-15, P<0.05). Sox6 KO mice were protected against renovascular hypertension (SBP, 114.5 vs. 131.1, SEM=5.31 n=13-15, P<0.01), and kidney injury during RAS. Furthermore, we found that the levels of creatinine clearance were preserved in Sox6 KO mice compared to WT littermates (2372 vs. 1341, SEM=342.3, n=4-5, P<0.05) during RAS. The levels of the kidney injury marker N-GAL were significantly lower in KO mice compared to WT littermates (1.3 vs. 2.7, SEM=0.38, n=6-8, P<0.01). Similarly, PRR receptor expression were significantly lower in KO compared to WT (1.23 vs. 0.72, SEM=0.33, n=2-5, P<0.01) during RAS. Conclusions: Our results show that knocking out Sox6 in renin expressing cells inhibits renovascular hypertension, renin, prorenin, PRR, and N-GAL expression, and preserve creatinine clearance induced by RAS. These results suggest that Sox6 has a new function in hypertension and kidney injury induced by RAS.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.