Abstract 023: Neuronal Overexpression of the Human (Pro)renin Receptor Increases Sympathetic Tone that is Masked by Upregulation of Endothelial Nitric Oxide Synthase

Abstract

The binding of prorenin to the (pro)renin receptor (PRR) induces non-proteolytic activation of prorenin and generation of angiotensin II (Ang II). PRR activation can also induce Ang II-independent signaling pathways. However, whether the Ang II-independent signaling pathways are important for blood pressure (BP) regulation is not known. To address this question, we created transgenic mice that overexpress the human PRR (hPRR) selectively in neurons (syn-PRR mice). Activated human prorenin (hPRO) cannot cleave endogenous mouse angiotensinogen to generate Ang II. Therefore, administration of hPRO to syn-PRR mice can be used to examine Ang II-independent PRR signaling. Intracerebroventricular infusion of hPRO increases BP in syn-PRR (ΔMAP: 23 ± 4.6) but has no effect on WT mice (ΔMAP: 2 ± 0.8). The hPRO-induced pressor response in syn-PRR mice is unaffected by treatment with the Ang II type 1 receptor blocker losartan (ΔMAP: 19 ± 5.2), suggesting that hPRR activation increases BP independent of Ang II. Interestingly, although basal MAP (101 ± 1.5 vs. 101 ± 1.3) and HR (552 ± 3.3 vs. 544 ± 7.3) are similar between syn-PRR and wildtype (WT) mice (n = 8/group), syn-PRR mice have increased basal cardiac (ΔHR: -68 ± 1.3 vs. -45 ± 1.4) and vasomotor (ΔMAP: -41 ± 2.1 vs. -29 ± 0.4) sympathetic tone. We hypothesized that the vasodilator-generating enzyme endothelial nitric oxide synthase (eNOS) activity was augmented in the periphery to compensate for increased sympathetic activity. qPCR revealed that eNOS mRNA is increased in mesenteric arteries from syn-PRR vs. WT mice (expression ratio 1.54 vs. 1.0). To examine eNOS activity we inhibited NO production by systemic administration of the L-arginine analogue L-NAME. L-NAME (400 mg/kg) was injected daily for 7 days. L-NAME treatment resulted in an increase in BP (MAP: 125 ± 5.2) in WT mice that normalized by 24 hrs post-injection (MAP: 106 ± 6.7). Interestingly, L-NAME treatment in syn-PRR mice resulted in an elevation of BP (MAP: 131 ± 5.1) that was sustained 24 hrs post-injection (MAP: 123 ± 2.6), suggesting that NOS activity is increased in syn-PRR mice. Together, these data provide evidence that neuronal overexpression of hPRR increases sympathetic activity that is masked by the subsequent upregulation of eNOS in the periphery.