Nephron‐Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. Issue 14 (17th July 2018)

• Record Type: Journal Article
• Authors: Gao, Yang; Stuart, Deborah; Takahishi, Takamune; Kohan, Donald E.
• Is Part Of: Journal of the American Heart Association. Volume 7:Issue 14(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-17
• Subjects: kidney -- nephron -- nitric oxide synthase -- sodium -- transporter; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.118.009236
• Languages: English
• ISSNs: 2047-9980

Abstract

Abstract : Background: In vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na + transport. Methods and Results: To assess nephron NOS3 relevance in vivo, knockout (KO) mice with doxycycline‐inducible nephron‐wide deletion of NOS3 were generated. During 1 week of salt loading, KO mice, as compared with controls, had higher arterial pressure and Na + retention, a tendency towards reduced plasma renin concentration, and unchanged glomerular filtration rate. Chronic high salt‐treated KO mice had modestly decreased total NCC and total SPAK/OSR1 versus controls, however percent phosphorylation of NCC (at T 53 ) and of SPAK/OSR1 was increased. In contrast, total and phosphorylated NKCC2 (at T 96/101 ) were suppressed by 50% each in KO versus control mice after chronic salt intake. In response to an acute salt load, KO mice had delayed urinary Na + excretion versus controls; this delay was completely abolished by furosemide, partially reduced by hydrochlorothiazide, but not affected by amiloride. After 4 hours of an acute salt load, phosphorylated and total NCC were elevated in KO versus control mice. Acute salt loading did not alter total NKCC2 or SPAK/OSR1 in KO versus control mice but increased the percent phosphorylation of NKCC2 (at T 96/101 and S 126 ) and SPAK/OSR1 in KO versus control mice. Conclusions: These findings indicate that nephron NOS3 is involved in blood pressure regulation and urinary Na + excretion during high salt intake. Nephron NOS3 appears to regulate NKCC2 and NCC primarily during acute salt loading. These effects of NOS3 may involve SPAK/OSR1 as well as other pathways.