Abstract 066: Renal-derived Human Sprr Induces Hypernatremia And Water Retention In Male Mice But Not Female Mice

Abstract

The soluble prorenin receptor (sPRR) plays an important role in fluid and electrolyte balance. In rodent models, sPRR contributes to aquaporin2(AQP2)-dependent antidiuretic action. However, there is a gap of knowledge concerning the functional role of locally produced human sPRR from the kidney. Hence, we evaluated the role of renal-derived human sPRR in fluid and electrolyte 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 and female mice were fed a standard diet for 10 months (n=8-11/group). Body weight was examined weekly, body composition monthly and water balance at study endpoint. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male and female mice validating the humanized mouse model.Renal-derived human sPRR did not change body weight in male or female mice (Male: CTL: 34±1, RHsPRR: 33±1 g; Female: CTL: 28±1, RHsPRR: 30±1 g) nor kidney function assessed by GFR (Male: CTL: 817±83, RHsPRR: 1088±163 μl/min/100gBW; Female: CTL: 1057±75, RHsPRR: 875±89 μl/min/100gBW). In male mice, renal-derived human sPRR significantly elevated plasma sodium (Male: CTL: 115±4, RHsPRR: 127±3 mmol/L; P<0.05) and ENaC gene expression (M: 1.7±0.7 and 3.7±0.9 2 -ΔΔCT , P<0.05). Urine flow rate was decreased (Male: CTL: 1.0±0.2, RHsPRR: 0.6±0.2 ml; P<0.05) and AQP2 protein expression was increased in male RHsPRR mice compared to CTL (M: 0.13±0.05 and 0.44±0.12 AU, P<0.05), suggesting that renal-derived human sPRR elicits hypernatremia by stimulating sodium reabsorption via ENaC-dependent mechanism and water reabsorption by AQP2 expression.In female mice, renal-derived human sPRR did not change plasma sodium (Female: CTL: 120±7, RHsPRR: 118±5 mmol/L), ENaC gene expression (F: 1.2±0.2 and 1.4±0.1 2 -ΔΔCT ), urine flow rate (Female: CTL: 0.4±0.1, RHsPRR: 0.5±0.1 ml) or AQP2 protein expression (F: 0.20±0.03 and 0.20±0.06 AU, P<0.05).Our data suggest that renal cortical and medullary human sPRR regulates water and electrolyte balance in a sex specific-manner. Translationally, human sPRR could be a promising therapeutic target to treat hypernatremia in men.