INTRODUCTION:
Renovascular hypertensive patients constitute 24.2% of all patients
with drug resistant hypertension (Benjamin, et al., 2014), a condition
characterized by persistent Stage I hypertension despite treatment with
three or more adequately dosed anti-hypertensive therapies (Carey, et
al., 2019). While the prevalence in the general population is low
(1-2%) (Derkx and Schalekamp, 1994), renovascular hypertension is more
common in elderly patients over age 65 (6.8%) and is present in nearly
40% of individuals with established peripheral or coronary artery
disease (Goldfarb, 2003), (Iglesias, et al., 2000). Approximately 90%
of renovascular hypertension stems from atherosclerotic renal artery
stenosis (ARAS) (Meurer et al., 2009),
(Sawicki, et al., 1991), (Tollefson and Ernst, 1991). ARAS leads to
obstruction of renal artery blood flow, resulting in
renin-angiotensin-aldosterone-system (RAAS) activation and subsequent
elevation of circulating blood plasma angiotensin II (Ang II)
(Goldblatt, et al., 1934). In response, the non-stenosed renal artery is
subjected to increased blood flow leading to augmented sodium and water
excretion by the kidney. This process, known as pressure natriuresis,
helps to mitigate increased fluid retention, volume overload, and
systemic blood pressure (Selkurt, 1951).
A main contributor to pressure natriuresis is endothelial-derived nitric
oxide (NO), which has been shown to play a critical role in the dilation
of the renal vasculature (Dautzenberg, et al., 2011), (Majid and Navar
2001), (Majid, et al., 1998), (O’Connor and Cowley 2010). NO diffuses to
vascular smooth muscle cells (VSMCs) where it binds its cognate
receptor, soluble guanylyl cyclase (sGC), which produces cGMP to elicit
vasorelaxation (Arnold, et al., 1977), (Kuo and Greengard 1970). Of
clinical importance, sGC modulating compounds, which enhance cGMP
production, are currently under investigation for treatment of renal and
cardiovascular diseases (Stasch, et al., 2015). In addition, we have
recently shown that basal sGC expression is regulated by the forkhead
box subclass O (FoxO) transcription factors in aortic VSMCs (Galley, et
al., 2019).
Based on this evidence, we hypothesized that renal artery smooth muscle
responds to elevated RAAS signaling with amplified sGC-mediated
production of cGMP. In this study, we used a two-kidney-one-clip (2K1C)
hypertension model, wherein blood flow to one renal artery is reduced
(Goldblatt, et al., 1934), as a model of RAAS activation and renal
hypertension. We find that renal smooth muscle responds to increased
levels of Ang II by increasing the expression of sGC. This increased sGC
expression occurs in an Ang II type 1 receptor (AT1R)
and FoxO transcription factor-dependent manner. Downstream, this results
in enhanced cGMP signaling and increased smooth muscle relaxation. These
studies are first to show that exposure of renal smooth muscle to
elevated Ang II results in a protective mechanism whereby sGC expression
is increased and leads to elevated cGMP production and vasorelaxation.