title: Collecting duct-specific knockout of nitric oxide synthase 3 impairs water excretion in a sex-dependent manner.
abstract: Nitric oxide (NO) inhibits collecting duct (CD) Na+and water reabsorption. Mice with CD-specific knockout (KO) of NO synthase 1 (NOS1) have salt-sensitive hypertension. In contrast, the role of NOS3 in CD salt and water reabsorption is unknown. Mice with CD NOS3 KO were generated with loxP-flanked exons 9-12 (encodes the calmodulin binding site) of the NOS3 gene and the aquaporin-2 promoter-Cre transgene. There were no differences between control and CD NOS3 KO mice, irrespective of sex, in food intake, water intake, urine volume, urinary Na+or K+excretion, plasma renin concentration, blood pressure, or pulse during 7 days of normal (0.3%), high (3.17%), or low (0.03%) Na+intake. Blood pressure was similar between genotypes during DOCA-high salt. CD NOS3 KO did not alter urine volume or urine osmolality after water deprivation. In contrast, CD NOS3 KO male, but not female, mice had lower urine volume and higher urine osmolality over the course of 7 days of water loading compared with control mice. Male, but not female, CD NOS3 KO mice had reduced urinary nitrite+nitrate excretion compared with controls after 7 days of water loading. Urine AVP and AVP-stimulated cAMP accumulation in isolated inner medullary CD were similar between genotypes. Western analysis did not reveal a significant effect of CD NOS3 KO on renal aquaporin expression. In summary, these data suggest that CD NOS3 may be involved in the diuretic response to a water load in a sex-specific manner; the mechanism of this effect remains to be determined.
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Deborah
authors.initials: D
authors.lastname: Stuart
authors.affiliation: Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Pollock
authors.affiliation: Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Takamune
authors.initials: T
authors.lastname: Takahishi
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah; donald.kohan@hsc.utah.edu.|George E. Whalen Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004326:Drinking / Q000502:physiology; D004435:Eating / Q000502:physiology; D005260:Female; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D009994:Osmolar Concentration; D012083:Renin / Q000097:blood; D012737:Sex Factors; D014867:Water / Q000378:metabolism*
chemical_list: D014867:Water; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D012083:Renin
keywords: collecting duct; gender; knockout; nitric oxide synthase; urinary water excretion