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.