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Angiotensin II augments renal vascular smooth muscle sGC expression via an AT1R - FoxO transcription factor signaling axis
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  • Joseph Galley,
  • Scott Hahn,
  • Megan Miller,
  • Brittany Durgin,
  • Edwin Jackson,
  • Sean Stocker,
  • A Straub
Joseph Galley
University of Pittsburgh
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Scott Hahn
University of Pittsburgh
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Megan Miller
University of Pittsburgh
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Brittany Durgin
University of Pittsburgh
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Edwin Jackson
University of Pittsburgh
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Sean Stocker
University of Pittsburgh
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A Straub
University of Pittsburgh
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Abstract

Background and Purpose: Reduced renal blood flow triggers activation of the renin-angiotensin-aldosterone system (RAAS) leading to renovascular hypertension. Renal vascular smooth muscle expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), modulates the vasodilatory response needed to control renal vascular tone and blood flow. Here, we tested if angiotensin II (Ang II) impacts sGC expression via an Ang II type 1 receptor (AT1R) -forkhead box subclass O (FoxO) transcription factor dependent mechanism. Experimental Approach: Using a murine 2-kidney-1-clip (2K1C) renovascular hypertension model, we measured renal artery vasodilatory function and sGC expression. Additionally, we conducted cell culture studies using rat renal pre-glomerular smooth muscle cells (RPGSMCs) to test the in vitro mechanistic effects of Ang II treatment on sGC expression and downstream function. Key Results: Contralateral, unclipped renal arteries in 2K1C mice showed increased NO – dependent vasorelaxation compared to sham control mice. Immunofluorescence studies revealed increased sGC protein expression in contralateral unclipped renal arteries over sham controls. RPGSMCs treated with Ang II caused a significant upregulation of sGC mRNA and protein expression as well as downstream sGC-dependent signaling. Ang II signaling effects on sGC expression occurred through an AT1R and FoxO transcription factor – dependent mechanism at both the mRNA and protein expression levels. Conclusion and Implications: Renal artery smooth muscle, in vivo and in vitro, upregulate expression of sGC following RAAS activity. In both cases, upregulation of sGC leads to elevated downstream cGMP signaling, suggesting a previously unrecognized protective mechanism to improve renal blood flow.

Peer review status:UNDER REVIEW

10 Sep 2020Submitted to British Journal of Pharmacology
10 Sep 2020Assigned to Editor
10 Sep 2020Submission Checks Completed
12 Sep 2020Reviewer(s) Assigned