Angiotensin II augments renal vascular smooth muscle sGC expression via an AT1 R – FoxO transcription factor signaling axis.

Please login or register to bookmark this article
Bookmark this %label%

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 (AT1 R)-forkhead box subclass O (FoxO) transcription factor dependent mechanism.Using a murine two-kidney-one-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.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 2K1C contralateral 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 AT1 R and FoxO transcription factor-dependent mechanism at both the mRNA and protein expression levels.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 in the uninjured contralateral renal artery.

View the full article @ British journal of pharmacology
Get PDF with LibKey

Authors: Joseph C Galley, Scott A Hahn, Megan P Miller, Brittany G Durgin, Edwin K Jackson, Sean D Stocker, Adam C Straub