Blood pressure maintenance in NHE3-deficient mice with transgenic expression of NHE3 in small intestine

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 288; no. 3; pp. R685 - R691
• Main Authors: Noonan, William T, Woo, Alison L, Nieman, Michelle L, Prasad, Vikram, Schultheis, Patrick J, Shull, Gary E, Lorenz, John N
• Format: Journal Article
• Language: English
• Published: United States 01.03.2005
• Subjects: Angiotensin II - blood; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Blood Pressure - drug effects; Blood Pressure - physiology; Dose-Response Relationship, Drug; Glomerular Filtration Rate - physiology; Homeostasis - physiology; Intestine, Small - metabolism; Losartan - pharmacology; Mice; Mice, Knockout; Mice, Transgenic; Natriuresis - physiology; Renal Circulation - physiology; Sodium, Dietary - administration & dosage; Sodium, Dietary - pharmacology; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers - metabolism; Sodium-Hydrogen Exchangers - physiology
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00209.2004

Departments of 1 Genome Science, 2 Molecular Genetics, Biochemistry, and Microbiology, and 3 Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; and 4 Department of Biological Sciences, Northern Kentucky University, Highland Heights, Kentucky Submitted 29 March 2004 ; accepted in final form 12 November 2004 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 (tg Nhe3 –/– ) 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 tg Nhe3 –/– mice than in wild-type controls (tg Nhe3 +/+ ) 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 tg Nhe3 –/– mice fed normal NaCl but not in those receiving high NaCl. Clearance studies revealed a blunted pressure-natriuresis response in tg Nhe3 –/– mice at lower blood pressures but a robust response at higher blood pressures. Autoregulation of GFR and RBF was normal in tg Nhe3 –/– mice. These results show that dietary NaCl loading normalizes blood pressure in awake tg Nhe3 –/– 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. telemetry; pressure natriuresis; autoregulation; Slc9a3; renal blood flow; glomerular filtration rate Address for reprint requests and other correspondence: J. N. Lorenz, Dept. of Molecular and Cellular Physiology, Univ. of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576 (E-mail: john.lorenz{at}uc.edu )