title: Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine.
abstract: NHE3 Na(+)/H(+) exchanger knockout (Nhe3(-/-)) mice have severe absorptive deficits in the kidney proximal tubule and intestinal tract. The resulting hypovolemia has confounded efforts to carefully evaluate the specific effects of NHE3 deficiency on kidney function. Development of mice with transgenic expression of NHE3 in the small intestine (tgNhe3(-/-)) has allowed us to analyze the role of renal NHE3 in overall maintenance of blood pressure, pressure natriuresis, and autoregulation of both glomerular filtration rate (GFR) and renal blood flow (RBF). Ambulatory blood pressure, measured by telemetry, was lower in tgNhe3(-/-) mice than in wild-type controls (tgNhe3(+/+)) when the mice were maintained on a normal NaCl diet but was normalized when they were provided with a high NaCl intake. Furthermore, administration of the AT1-receptor blocker losartan showed that circulating ANG II plays a major role in maintaining blood pressure in tgNhe3(-/-) mice fed normal NaCl but not in those receiving high NaCl. Clearance studies revealed a blunted pressure-natriuresis response in tgNhe3(-/-) mice at lower blood pressures but a robust response at higher blood pressures. Autoregulation of GFR and RBF was normal in tgNhe3(-/-) mice. These results show that dietary NaCl loading normalizes blood pressure in awake tgNhe3(-/-) mice and that alterations in NHE3 activity are not essential for normal autoregulation of GFR and RBF. Furthermore, the data strongly support the hypothesis that NHE3 plays an important role in the diuretic and natriuretic responses to increases in blood pressure but also show that mechanisms not involving NHE3 mediate pressure natriuresis in the higher range of blood pressures studied.
authors.affiliation: Department of Genome Science, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Noonan
authors.forename: Alison L
authors.initials: AL
authors.lastname: Woo
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Nieman
authors.forename: Vikram
authors.initials: V
authors.lastname: Prasad
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Schultheis
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
mesh_terms: D000804:Angiotensin II / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005919:Glomerular Filtration Rate / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009318:Natriuresis / Q000502:physiology; D012079:Renal Circulation / Q000502:physiology; D012982:Sodium, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C000613386:Slc9a3 protein, mouse; D012982:Sodium, Dietary; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; D019808:Losartan