title: Collecting duct-specific knockout of renin attenuates angiotensin II-induced hypertension.
abstract: The physiological and pathophysiological significance of collecting duct (CD)-derived renin, particularly as it relates to blood pressure (BP) regulation, is unknown. To address this question, we generated CD-specific renin knockout (KO) mice and examined BP and renal salt and water excretion. Mice containing loxP-flanked exon 1 of the renin gene were crossed with mice transgenic for aquaporin-2-Cre recombinase to achieve CD-specific renin KO. Compared with controls, CD renin KO mice had 70% lower medullary renin mRNA and 90% lower renin mRNA in microdissected cortical CD. Urinary renin levels were significantly lower in KO mice (45% of control levels) while plasma renin concentration was significantly higher in KO mice (63% higher than controls) during normal-Na intake. While no observable differences were noted in BP between the two groups with varying Na intake, infusion of angiotensin II at 400 ng·kg(-1)·min(-1) resulted in an attenuated hypertensive response in the KO mice (mean arterial pressure 111 ± 4 mmHg in KO vs. 128 ± 3 mmHg in controls). Urinary renin excretion and epithelial Na(+) channel (ENaC) remained significantly lower in the KO mice following ANG II infusion compared with controls. Furthermore, membrane-associated ENaC protein levels were significantly lower in KO mice following ANG II infusion. These findings suggest that CD renin modulates BP in ANG II-infused hypertension and these effects are associated with changes in ENaC expression.
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah; and 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; and.
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; and.
authors.forename: Sara
authors.initials: S
authors.lastname: Rees
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah; and.
authors.forename: Alfred Van
authors.initials: AV
authors.lastname: Hoek
authors.affiliation: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.affiliation: Division of Nephrology and Hypertension, University of Utah Health Sciences Center, Salt Lake City, Utah; and.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000096:biosynthesis; D005260:Female; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D017673:Sodium Chloride, Dietary / Q000494:pharmacology
chemical_list: D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D012083:Renin
keywords: collecting duct; hypertension; renin