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    In vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na+ transport. 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 T53) and of SPAK/OSR1 was increased. In contrast, total and phosphorylated NKCC2 (at T96/101) 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 T96/101 and S126) and SPAK/OSR1 in KO versus control mice. 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. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

    Citation

    Yang Gao, Deborah Stuart, Takamune Takahishi, Donald E Kohan. Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. Journal of the American Heart Association. 2018 Jul 11;7(14)

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    PMID: 29997131

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