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.