title: 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.
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah; nirupama.ramkumar@hsc.utah.edu.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Ramkumar
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors.forename: Deborah
authors.initials: D
authors.lastname: Stuart
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors.forename: Matias
authors.initials: M
authors.lastname: Calquin
authors.affiliation: Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and.
authors.forename: Syed
authors.initials: S
authors.lastname: Quadri
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors.forename: Shuping
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors.forename: Alfred N
authors.initials: AN
authors.lastname: Van Hoek
authors.affiliation: Department of Medicine, University of Virginia Health System, Charlottesville, Virginia; and.
authors.forename: Helmy M
authors.initials: HM
authors.lastname: Siragy
authors.affiliation: Department of Medicine II, Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Ichihara
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah;
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000818:Animals; D005260:Female; D007668:Kidney / Q000473:pathology / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D006180:Proton-Translocating ATPases / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D014556:Urine; D014867:Water / Q000502:physiology*; D000093342:Prorenin Receptor
chemical_list: C583530:ATP6AP2 protein, mouse; D011956:Receptors, Cell Surface; D014867:Water; D006180:Proton-Translocating ATPases; D000093342:Prorenin Receptor
keywords: nephron knockout; prorenin receptor; urine concentration