Abstract MP34: Collecting Duct Cells-derived Human Sprr Impairs The Antihypertensive Effects Of Losartan And Upregulates Erk1/2 And Aqp2 Expression

Abstract

Recent studies showed that soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation and in water balance. In rodent models, sPRR contributes to AngII production by increasing renin activity, systolic blood pressure (SBP) and aquaporin2 (AQP2)-dependent antidiuretic action. However, there is a gap of knowledge concerning the functional role of locally produced sPRR from the kidney. Therefore, we evaluated the kidney-derived human sPRR role in SBP control and fluid homeostasis. Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male mice were fed a standard diet for 10 months (n=8-11/group). Body weight and urine volume were examined and SBP measured by radiotelemetry. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male mice validating the humanized mouse model. Body weight did not change and 24hr-SBP was similar between CLT and RHsPRR mice (128±2 and 122±5 mmHg, respectively). However, the chronic response to losartan treatment was reduced in RHsPRR compared to CTL (ΔSBP: CTL: -9±3; RHsPRR: -5±1 mmHg, P<0.05). Kidney-derived human sPRR did not change GFR (838±75 vs 1088±163 μl/min/100g BW) and urinary vasopressin (0.62±0.21; 0.72±0.20 ng/mg creatinine), while modestly decreasing urine excretion rate by ~40% (CTL: 1.04±0.20; RHsPRR: 0.57±0.25 ml/day). Furthermore, RHsPRR mice had higher AQP2 protein expression in renal cortex (CTL: 0.24±0.07; RHsPRR: 4.11±0.70 AU, P<0.05) and medulla (CTL: 0.11±0.04; RHsPRR: 4.03±1.74 AU, P<0.05) than CTL mice. Kidney-derived human sPRR significantly increased phosphorylation of ERK 1/2 in the cortex compared to CTL (CTL: 5.4±1.0; RHsPRR: 9.2±1.4 AU, P<0.05), an MAPK involved in the regulation of water balance. In addition, RHsPRR mice showed increased plasma osmolality compared to CTL mice (CTL: 349±2; RHsPRR: 357±2 mOsm/kg, P<0.05). Overall, our data suggest that renal human sPRR could contribute to the increase in plasma tonicity by promoting the activation of ERK1/2-AQP2 pathway. Whether this signaling is associated with impaired antihypertensive effects of AT1R blockage remains under investigation.