Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor

Abstract

Until now, renin-angiotensin system (RAS) hyperactivity was largely thought to result from angiotensin II (Ang II) dependent stimulation of the Ang II type 1 receptor (AT1R). Here we assessed the role of soluble (pro)renin receptor (sPRR), a product of site-1 protease-mediated cleavage of (pro)renin receptor (PRR), as a possible ligand of the AT1R in mediating: (i) endothelial cell dysfunction in vitro; and (ii) arterial dysfunction in mice with diet-induced obesity. Primary human umbilical vein endothelial cells (HUVECs) treated with a recombinant histidine-tagged sPRR (sPRR-His) exhibited IκBα degradation concurrent with NF-κB p65 activation. These responses were secondary to sPRR-His evoked elevations in Nox4-derived H2O2 production that resulted in inflammation, apoptosis and reduced NO production. Each of these sPRR-His-evoked responses was attenuated by AT1R inhibition using Losartan (Los) but not ACE inhibition using captopril (Cap). Further mechanistic exploration revealed that sPRR-His activated AT1R downstream Gq signaling pathway. Immunoprecipitation coupled with autoradiography experiments and radioactive ligand competitive binding assays indicate sPRR directly interacts with AT1R via Lysine199 and Asparagine295. Important translational relevance was provided by findings from obese C57/BL6 mice that sPRR-His evoked endothelial dysfunction was sensitive to Los. Besides, sPRR-His elevated blood pressure in obese C57/BL6 mice, an effect that was reversed by concurrent treatment with Los but not Cap. Collectively, we provide solid evidence that the AT1R mediates the functions of sPRR during obesity-related hypertension. Inhibiting sPRR signaling should be considered further as a potential therapeutic intervention in the treatment and prevention of cardiovascular disorders involving elevated blood pressure.

Adipose Tissue-Endothelial Cell Interactions in Obesity-Induced Endothelial Dysfunction

“…Soluble (pro)renin receptor induced ED and hypertension by activating AT1R leading to RAS hyperactivity in mouse models of obesity (41).…”

The Soluble (Pro)Renin Receptor in Health and Diseases: Foe or Friend?

“…sPRR from the medium of cultured human umbilical vein endothelial cells (HUVECs) (Biswas KB et al, 2011) or Chinese hamster ovary cells overexpressed human PRR (Yoshikawa A et al, 2011), increased the renin activity of the (Xu C et al, 2020) and increased aldosterone release and CYP11B2 protein expression in primary cultured rat inner medullary collecting duct (IMCD) cells (Xu C et al, 2016). Recently, sPRR has been reported to directly bind AT1R to activate NOX 4 /H 2 O 2 signaling pathway that contributes to endothelial dysfunction (Fu Z et al, 2021). Thus, these in vitro results indicate the stimulation effect of sPRR on local RAS.…”

“…While the increase of BP in sPRR-infused male obese mice may be attributed to the impaired baroreflex sensitivity and the activation of the sympathetic nervous system, given by the observations that chlorisondamine (a ganglionic blocker) treatment downregulated BP in these mice (Gatineau E et al, 2019b). Of note, this is challenged by a recent study that concurrent treatment with losartan reversed sPRR-His-elevated blood pressure in obese C57/BL6 male mice (Fu Z et al, 2021). The reasons for this discrepancy are unclear.…”

Soluble (pro)renin receptor: a novel ligand for angiotensin II type 1 receptor?

“…Interestingly, plasma sPRR levels were reported to be elevated in patients with atherosclerosis [7], heart failure [8], and hypertension [9]. Although plasma sPRR levels are clinically important, the study by Fu et al [10] appears to be a stepping-stone to understanding the molecular mechanism by which sPRR may contribute to CVD.…”

“…This is because the activation of AT1R has been thought to be mostly dependent on Ang II, the major physiological ligand [3]. However, Fu et al [10] challenged this conventional view by evaluating the role of sPRR as a ligand for the AT1R. When sPRR was administered to human umbilical vein endothelial cells (HUVECs), the production of Nox4-derived H 2 O 2 was increased, leading to inflammation, apoptosis, and decreased nitric oxide production (Figure 1A).…”