NEPHRON SPECIFIC DELETION OF PRORENIN RECEPTOR MODULATES WATER AND SODIUM HOMEOSTASIS

Abstract

The prorenin receptor (PRR), a newly discovered component of the RAS, has been localized to the collecting duct, distal convoluted tubule, proximal tubule and podocytes. Targeted deletion of PRR, whether global or cell-specific, has resulted in either early lethality or organ malformation due to abnormal lysosomal acidification. Consequently, the physiological significance of nephron derived PRR is unclear. To examine this, we developed mice with inducible nephron-wide PRR deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP flanked PRR alleles to achieve nephron-specific PRR disruption after doxycycline induction. Adult Pax8-rtTA/LC-1/floxed PRR mice were treated with doxycycline 2 mg/ml in drinking water for 12 days and studied 4 weeks after treatment. Nephron specific PRR KO mice have normal survival and no histological defects in the kidney. Compared to controls, PRR knockout (KO) mice demonstrated 60% lower PRR mRNA levels and significantly lower PRR immunofluorescence. Under both Na intake, PRR KO mice had significantly lower urine osmolality, higher water intake and higher urine volume compared to controls. No notable differences were seen in body weight or food intake. PRR KO mice had higher Na excretion compared to controls on days 1 and 2 of change from normal to low Na diet but similar Na excretion on other days of low Na intake. Finally, no detectable differences in BP were noted between the two groups on normal or low Na diet (7 days each). These data suggest that nephron PRR can potentially modulate water and sodium homeostasis. * P < 0.05 Normal Na diet (0.25%) lLow Na diet (0.03%) Controls PRR KO Controls PRR KO Body weight (g) 26.9 ± 3.1 24.2 ± 1.6 26.3 ± 2.7 23.3 ± 1.4 Food intake (g) 5.2 ± 0.3 4.4 ± 0.3 4.0 ± 0.3 3.8 ± 0.3 Water intake (ml) 3.9 ± 0.6 8.9 ± 1.3* 3.9 ± 0.4 7.2 ± 0.8* Urine Volume (ml/day) 1.7 ± 0.2 6.0 ± 1.0* 1.3 ± 0.4 4.4 ± 0.7* Urine osmolality (mosm Kg/H2O) 3133 ± 396 1325 ± 426* 1679 ± 270 976 ± 320* Urine NaV (μmol/d) 222 ± 28 236 ± 32 42 ± 6 66 ± 10* Urine KV(μmol/d) 311 ± 32 298 ± 28 184 ± 31 236 ± 20 Systolic blood pressure (mm Hg) 119 ± 3 122 ± 4 118 ± 4 122 ± 2 Diastolic blood pressure (mm Hg) 94 ± 3 96 ± 3 93 ± 2 95 ± 3