Elevated prorenin levels associate with microvascular complications in patients with diabetes mellitus. Prorenin may generate angiotensin I at tissue sites, possibly by binding to the (P)RR. We evaluated this possibility in diabetic TGR(mREN2)27 rats.

Rats made diabetic with streptozotocin were treated with vehicle, the renin inhibitor aliskiren with(out) the (P)RR antagonist HRP. Blood pressure and heart rate were monitored by telemetry. After sacrifice mesenteric arteries (MA) were used to evaluate vascular reactivity. relaxed MA of vehicle-treated rats. The NO synthase inhibitor L-NAME partially blocked the effect of ACh, whereas adding Tram34+apamin (inhibitors of intermediate/small conductance Ca2+-dependent K+ channels) on top of L-NAME reversed the relaxant ACh response into a contractile effect. Aliskiren did not alter the relaxant effect of ACh, nor the degree of blockade by L-NAME, but prevented the contractile response to ACh in the presence of L-NAME, Tram34+apamin. Yet, following co-treatment with HRP, the latter response returned, suggesting that HRP counteracts the aliskiren-induced downregulation of ACh-induced constriction, either by upregulating contractile muscarinic receptors and/or by enhancing the release of endothelium-derived contractile factor(s). Treatment did not alter the NO-responsiveness of the vascular smooth muscle cells, evaluated with the NO donor SNAP. Endothelin-1 constricted MA identically with and without treatment. Yet, the ETA receptor antagonist BQ123 inhibited this effect in aliskiren+HRP-treated rats only, suggesting selective upregulation of ETA receptors by HRP. HRP upregulates ETA receptors and the contractile response to ACh, thereby counteracting the beneficial vascular effects of aliskiren. This occurs in a blood pressure-independent manner, and argues against detrimental effects of (P)RR-prorenin interaction.