title: Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines.
abstract: The role of Na(+/)H(+) exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3(-/-)) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3(+/+)) and tgNhe3(-/-) mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3(-/-) mice (P < 0.01). Basal glomerular filtration rate, 24 h urine excretion, urinary Na(+) excretion, urinary K(+) excretion, and urinary Cl(-) excretion were significantly lower in tgNhe3(-/-) mice (P < 0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na(+)/HCO3 cotransporter, the α1 subunit isoform of Na(+)/K(+)-ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex of tgNhe3(-/-) mice (P < 0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3(+/+), as expected, but all of these responses to ANG II were attenuated in tgNhe3(-/-) mice (P < 0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension.
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Xiao C
authors.initials: XC
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Elisa
authors.initials: E
authors.lastname: Miguel-Qin
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio jzhuo@umc.edu.
authors.forename: Jia L
authors.initials: JL
authors.lastname: Zhuo
keywords: Angiotensin II; NHE3; hypertension; intestines; kidney