Abstract 063: Soluble (Pro)renin Receptor Acts Via Direct Activation Of Angiotensin Type 1 Receptor To Enhance Renal Aquaporin-2 Expression And Urine Concentrating Capability

Abundant evidence has established an essential role of collecting duct (pro)renin receptor (PRR) in regulation of aquaporin-2 (AQP-2) expression and urine concentrating capability. Moreover, such AQP2-regulating and antidiuretic action of PRR is mediated by its cleavage product, the soluble PRR (sPRR). However, the mechanism of action of sPRR in this setting remains incompletely understood. In light of our recent report of direct interaction of sPRR and angiotensin type 1 receptor (AT1R) in the vascular endothelial cells, we examined the hypothesis that sPRR signals via AT1R in the kidney. In primary rat inner medullary collecting duct cells, exposure to a recombinant sPRR (termed as sPRR-His) at 10 nM for 24 h induced 4 fold increase in AQP2 protein abundance, which was blunted by `~50% by pretreatment with losartan. In C57/BL6 mice, administration of the V2R antagonist (OPC at 30 mg/kg/d via gavage for 3 days) resulted in symptoms of nephrogenic diabetes insipidus (NDI), including polydipsia, polyuria, and hypoosmotic urine, all of which were improved by subcutaneous infusion of sPRR-His at 30 μg/kg/d via minipump (urine volume [ml]: 5.3 ± 0.2 vs. 3.3 ± 0.3, n =5, p < 0.01; urine osmolality [Osm/kg. H2O]: 428.6 ± 29.2 vs. 704.6 ± 24.2, n =5, p < 0.01). Administration of losartan (5 mg/kg/d) almost completely reversed the therapeutic effect of sPRR-His (urine volume [ml]: 4.7 ± 0.2; urine osmolality [Osm/kg. H2O]: 486 ± 16.1). Immunoblotting demonstrated that sPRR-His treatment restored OPC-induced reduction of AQP2 protein abundance, which was reversed by losartan. Together, sPRR interacted with AT1R to control renal AQP2 expression and urine concentrating capability.