Renal Derived Human sPRR Increases Plasma Osmolality and Aquaporin 2 Expression in Male but Not in Female Mice

Abstract

Several studies have shown that soluble prorenin receptor (sPRR) plays an important role in fluid and electrolyte balance. In rodent models, water deprivation led to an increase in sPRR in the kidney. Our laboratory previously showed that infusion of mouse recombinant sPRR increased urinary vasopressin but did not change water intake and urine flow rate in female mice. Moreover, a counter regulatory increase in plasma sPRR due to knockdown of prorenin receptor (PRR) in the adipose tissue decreased urine flow rate in both male and female mice. However, there is a gap of knowledge concerning the functional role of locally produced sPRR from the kidney. Additionally, the role of human sPRR in fluid and electrolyte balance has not been evaluated. Therefore, 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, body composition and water balance were assessed. 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 sPRR mouse model.Renal derived human sPRR did not change body weight (BW) in male or female mice (Male: CTL: 34±1, RHsPRR: 33±1g; Female: CTL: 28±1, RHsPRR: 30±1g) and kidney function (eGFR: Male: CTL: 817±83, RHsPRR: 1088±163µl/min/100gBW; Female: CTL: 1057±75, RHsPRR: 875±89µl/min/100gBW). Renal derived human sPRR did not significantly increase circulating sPRR (Male: CTL: 3995±643, RHsPRR: 4342±500pg/ml; Female: CTL: 3479±194, RHsPRR: 3948±238pg/ml) suggesting that kidneys are not a source of circulating sPRR. Renal‐derived human sPRR increased plasma osmolality in males but not females (Male: CTL: 328±3, RHsPRR: 407±55mOsm/kg, P<0.05; Female: CTL: 327±3, RHsPRR: 327±2 mOsm/kg) but did not change urine osmolality in both males and females (Male: CTL: 3855±153, RHsPRR: 3881±275 mOsm/kg; Female: CTL: 3730±341, RHsPRR: 3247±256 mOsm/kg). Moreover, renal derived human sPRR tended to increase urinary vasopressin in males but not females (Male: CTL: 373±70, RHsPRR: 971±369pg/day, P=0.056; Female: CTL: 584±140, RHsPRR: 1873±567pg/day). In line with those results, urine flow rate decreased by ~50% in males but not females (Male: CTL: 1.03±0.2, RHsPRR: 0.57±0.2ml/day; Female: CTL: 0.42±0.1, RHsPRR: 0.47±0.1ml/day). Renal AQP2 expression increased in males while in females, AQP2 expression decreased (Male: CTL: 9.1±3.0, RHsPRR: 43.8±14.0 AU, P<0.05; Female: CTL: 6.0±3.0, RHsPRR: 0.9±0.4 AU). Renal derived human sPRR also significantly increased phosphorylation of ERK1/2 in the cortex of both males and females (Male: CTL: 0.42±0.1, RHsPRR: 0.81±0.2 AU; Female: CTL: 0.40±0.1, RHsPRR: 0.63±0.1 AU). Overall, our data suggest that human sPRR exerts an antidiuretic effect in a sex‐dependent manner and could contribute to the increase in plasma tonicity by promoting the activation of ERK1/2‐AQP2 pathway in male mice.