title: Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension.
abstract: Nitric oxide (NO) is an important negative modulator of tubuloglomerular feedback responsiveness. We recently found that macula densa expresses α-, β-, and γ-splice variants of neuronal nitric oxide synthase 1 (NOS1), and NOS1β expression in the macula densa increases on a high-salt diet. This study tested whether upregulation of NOS1β expression in the macula densa affects sodium excretion and salt-sensitive hypertension by decreasing tubuloglomerular feedback responsiveness. Expression levels of NOS1β mRNA and protein were 30- and five-fold higher, respectively, than those of NOS1α in the renal cortex of C57BL/6 mice. Furthermore, macula densa NO production was similar in the isolated perfused juxtaglomerular apparatus of wild-type (WT) and nitric oxide synthase 1α-knockout (NOS1αKO) mice. Compared with control mice, mice with macula densa-specific knockout of all nitric oxide synthase 1 isoforms (MD-NOS1KO) had a significantly enhanced tubuloglomerular feedback response and after acute volume expansion, significantly reduced GFR, urine flow, and sodium excretion. Mean arterial pressure increased significantly in MD-NOS1KO mice (P<0.01) but not NOS1flox/flox mice fed a high-salt diet. After infusion of angiotensin II, mean arterial pressure increased by 61.6 mmHg in MD-NOS1KO mice versus 32.0 mmHg in WT mice (P<0.01) fed a high-salt diet. These results indicate that NOS1β is a primary NOS1 isoform expressed in the macula densa and regulates the tubuloglomerular feedback response, the natriuretic response to acute volume expansion, and the development of salt-sensitive hypertension. These findings show a novel mechanism for salt sensitivity of BP and the significance of tubuloglomerular feedback response in long-term control of sodium excretion and BP.
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida; Departments of Physiology and Biophysics and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida;
authors.forename: Jin
authors.initials: J
authors.lastname: Wei
authors.affiliation: Departments of Physiology and Biophysics and.
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.affiliation: Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi;
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.affiliation: Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi;
authors.forename: Ying
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Departments of Physiology and Biophysics and.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Departments of Physiology and Biophysics and.
authors.forename: Eddie Y
authors.initials: EY
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiovascular and Renal Research, University of Southern Denmark, Odense, Denmark;
authors.forename: Pernille B Laerkegaard
authors.initials: PB
authors.lastname: Hansen
authors.affiliation: Pharmacology, University of Mississippi Medical Center, Jackson, Mississippi;
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.affiliation: Departments of Physiology and Biophysics and.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Juncos
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida;
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pollock
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.affiliation: Departments of Physiology and Biophysics and.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida;
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa, Florida; Departments of Physiology and Biophysics and ruisheng@health.usf.edu.
authors.forename: Ruisheng
authors.initials: R
authors.lastname: Liu
mesh_terms: D000818:Animals; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology* / Q000517:prevention & control; D007606:Juxtaglomerular Apparatus / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052248:Nitric Oxide Synthase Type I / Q000502:physiology* / Q000627:therapeutic use; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
chemical_list: D017673:Sodium Chloride, Dietary; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
keywords: NOS1; hypertension; macula densa; salt-sensitive; tubuloglomerular feedback