Nephron-specific deletion of the prorenin receptor causes a urine concentration defect

Abstract

The prorenin receptor (PRR), a recently discovered component of the renin-angiotensin system, is expressed in the nephron in general and the collecting duct in particular. However, the physiological significance of nephron PRR remains unclear, partly due to developmental abnormalities associated with global or renal-specific PRR gene knockout (KO). Therefore, we developed mice with inducible nephron-wide PRR deletion using Pax8-reverse tetracycline transactivator and LC-1 transgenes and loxP flanked PRR alleles such that ablation of PRR occurs in adulthood, after induction with doxycycline. Nephron-specific PRR KO mice have normal survival to ∼1 yr of age and no renal histological defects. Compared with control mice, PRR KO mice had 65% lower medullary PRR mRNA and protein levels and markedly diminished renal PRR immunofluorescence. During both normal water intake and mild water restriction, PRR KO mice had significantly lower urine osmolality, higher water intake, and higher urine volume compared with control mice. No differences were seen in urine vasopressin excretion, urine Na(+) and K(+) excretion, plasma Na(+), or plasma osmolality between the two groups. However, PRR KO mice had reduced medullary aquaporin-2 levels and arginine vasopressin-stimulated cAMP accumulation in the isolated renal medulla compared with control mice. Taken together, these results suggest nephron PRR can potentially modulate renal water excretion.

Water Deprivation Increases (Pro)renin Receptor Levels in the Kidney and Decreases Plasma Concentrations of Soluble (Pro)renin Receptor

“…Expression levels of (P)RR in the kidney were up-regulated in rats with congestive heart failure or chronic renal failure due to 5/6 nephrectomy (Hirose et al , 2010. Ramkumar et al (2015) showed that nephron-specific deletion of the (P)RR caused a urine concentration defect, and suggested that nephron (P)RR can potentially modulate renal water excretion. We have recently reported that high salt intake upregulates (P)RR expression in rat nephron (Rong et al 2015).…”

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

“…A functional role of PRR in regulating renal aquaporin 2 (AQP2) expression and urine-concentrating capability has been revealed by analysis of mice with conditional deletion of PRR in the nephron (15) and the CD (14). However, whether the antidiuretic action of CD PRR is conferred by sPRR remains elusive.…”

The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome

“…26 Similarly, infusion of PRR short hairpin RNA in the renal medulla decreased expression of the epithelial sodium channel (ENaC) in rats (although the effect on BP was not examined). 32 To delineate the role of nephron PRR in BP regulation, we developed an inducible renal tubule PRR KO mouse 33 to avoid the deleterious effects of PRR deletion on organ development. Renal tubule PRR KO mice had similar BP as control mice under varying sodium intake but had an attenuated hypertensive response with reduced renal ENaC expression after Ang II infusion.…”

“…Renal tubular PRR also modulates water reabsorption through Ang II-dependent and Ang II-independent mechanisms. 33,[37][38][39] Recent studies have shown that the PRR regulates vasopressin-stimulated AQP2 expression via activation of prostaglandin EP4 receptor 39 and the Wnt/b-catenin pathway. 38 A fundamental question is whether the intercalated and/or principal cell PRR modulates renal sodium and water reabsorption.…”