High-plasma soluble prorenin receptor is associated with vascular damage in male, but not female, mice fed a high-fat diet

Abstract

Plasma soluble prorenin receptor (sPRR) displays sexual dimorphism and is higher in women with type 2 diabetes mellitus (T2DM). However, the contribution of plasma sPRR to the development of vascular complications in T2DM remains unclear. We investigated if plasma sPRR contributes to sex differences in the activation of the systemic renin-angiotensin-aldosterone system (RAAS) and vascular damage in a model of high-fat diet (HFD)-induced T2DM. Male and female C57BL/6J mice were fed either a normal fat diet (NFD) or an HFD for 28 weeks to assess changes in blood pressure, cardiometabolic phenotype, plasma prorenin/renin, sPRR, and Ang II. After completing dietary protocols, tissues were collected from males to assess vascular reactivity and aortic reactive oxygen species (ROS). A cohort of male mice was used to determine the direct contribution of increased systemic sPRR by infusion. To investigate the role of ovarian hormones, ovariectomy (OVX) was performed at 32 weeks in females fed either a NFD or HFD. Significant sex differences were found after 28 weeks of HFD, where only males developed T2DM and increased plasma prorenin/renin, sPRR, and Ang II. T2DM in males was accompanied by non-dipping hypertension, carotid artery material stiffening, and aortic ROS. sPRR infusion in males induced vascular thickening instead of material stiffening caused by HFD-induced T2DM. While intact females were less prone to T2DM, OVX increased plasma prorenin/renin, sPRR, and SBP. These data suggest that sPRR is a novel indicator of systemic RAAS activation and reflects the onset of vascular complications during T2DM regulated by sex.

Renal-Derived Human sPRR Does Not Increase Blood Pressure in High Fat Diet Mice

“…The role of sPRR in obesityrelated hypertension in male mice has been well demonstrated (52)(53)(54). Male mice fed a high fat diet for 32 weeks showed elevated plasma sPRR was associated with activation of systemic RAS, vascular damage, and non-dipping hypertension (54). Similarly, obese male mice fed 32 weeks of HFD and infused with sPRR had hypertension due to endothelial dysfunction mediated by the activation of AT1R (52).…”

“…Additionally, obese male CD-HsPRR mice have an increase in α-and -ENaC protein expression along with renin and AT1R mRNA expression. The role of sPRR in obesityrelated hypertension in male mice has been well demonstrated (52)(53)(54). Male mice fed a high fat diet for 32 weeks showed elevated plasma sPRR was associated with activation of systemic RAS, vascular damage, and non-dipping hypertension (54).…”

Urinary Angiotensinogen Displays Sexual Dimorphism in Non-Diabetic Humans and Mice with Overweight

“…We have recently reported that the augmentation of uAGT was associated with high levels of soluble (pro)renin receptor (sPRR) in men but not in women with type 2 diabetes mellitus [ 17 ]. The PRR is involved in the progression of diabetic kidney disease highlighting the relevance of sPRR as a potential biomarker of kidney disease [ 21 , 22 , 23 , 24 ]. Indeed, uAGT is significantly higher in those patients with higher levels of plasma sPRR than in patients with low levels of uAGT.…”

“…This difference was significant only in men [ 20 ]. Similarly, an HFD for 28 weeks in male mice leads to a T2DM phenotype and concomitant increased sPRR in plasma, suggesting that sPRR may indicate the status of systemic RAS activation and the onset of vascular complications during T2DM in a sex-dependent manner [ 24 ]. These findings are important, as Sartori-Valinotti et al demonstrated that females are protected from renal injury when given Ang II and high salt, whereas the increase in renal injury and oxidative stress in males may play a role in exacerbation of hypertension with Ang II and high salt.…”