title: Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport.
abstract: The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na(+) excretion and investigated the signaling mechanisms by which PRR regulates Na(+) balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na(+) diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na(+) balance with normal- and low-Na(+) intake. PRR KO mice had an attenuated hypertensive response and reduced Na(+) retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na(+) channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na(+) wasting and reduces the hypertensive response to ANG II.
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: Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Mironova
authors.affiliation: Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Bugay
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: Nikita
authors.initials: N
authors.lastname: Abraham
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: Department of Physiology, University of Texas Health Science Center, San Antonio, Texas; and.
authors.forename: James D
authors.initials: JD
authors.lastname: Stockand
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah; Veterans Affairs Medical Center, Salt Lake City, Utah;
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D004039:Diet, Sodium-Restricted; D004847:Epithelial Cells / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012964:Sodium / Q000378:metabolism*; D012982:Sodium, Dietary / Q000494:pharmacology; D000093342:Prorenin Receptor
chemical_list: D053503:Epithelial Sodium Channels; D011956:Receptors, Cell Surface; D012982:Sodium, Dietary; D000804:Angiotensin II; D012964:Sodium; D051058:Oncogene Protein v-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D000093342:Prorenin Receptor
keywords: angiotensin II; blood pressure; prorenin receptor; sodium transport