Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect

• Published in: American journal of physiology. Renal physiology Vol. 284; no. 6; pp. F1190 - F1198
• Main Authors: Woo, Alison L, Noonan, William T, Schultheis, Patrick J, Neumann, Jonathan C, Manning, Patrice A, Lorenz, John N, Shull, Gary E
• Format: Journal Article
• Language: English
• Published: United States 01.06.2003
• Subjects: Aldosterone - blood; Animals; Blood Pressure - physiology; Blotting, Northern; Diet, Sodium-Restricted; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Extracellular Space - physiology; Glomerular Filtration Rate; Heart Rate - physiology; Hypotension - physiopathology; Intestinal Absorption - genetics; Intestinal Absorption - physiology; Intestine, Small - metabolism; Kidney - physiology; Mice; Mice, Transgenic; Rats; Renal Circulation - physiology; RNA - biosynthesis; RNA - isolation & purification; Sodium - pharmacology; Sodium-Hydrogen Exchanger 3; Sodium-Hydrogen Exchangers - genetics; Sodium-Hydrogen Exchangers - physiology
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00418.2002

The degree to which loss of the NHE3 Na(+)/H(+) exchanger in the kidney contributes to impaired Na(+)-fluid volume homeostasis in NHE3-deficient (Nhe3(-/-)) mice is unclear because of the coexisting intestinal absorptive defect. To more accurately assess the renal effects of NHE3 ablation, we developed a mouse with transgenic expression of rat NHE3 in the intestine and crossed it with Nhe3(-/-) mice. Transgenic Nhe3(-/-) (tgNhe3(-/-)) mice tolerated dietary NaCl depletion better than nontransgenic knockouts and showed no evidence of renal salt wasting. Unlike nontransgenic Nhe3(-/-) mice, tgNhe3(-/-) mice tolerated a 5% NaCl diet. When fed a 5% NaCl diet, tgNhe3(-/-) mice had lower serum aldosterone than tgNhe3(-/-) mice on a 1% NaCl diet, indicating improved extracellular fluid volume status. Na(+)-loaded tgNhe3(-/-) mice had sharply increased urinary Na(+) excretion, reflective of increased absorption of Na(+) in the small intestine; nevertheless, they remained hypotensive, and renal studies showed a reduction in glomerular filtration rate (GFR) similar to that observed in nontransgenic Nhe3(-/-) mice. These data show that reduced GFR, rather than being secondary to systemic hypovolemia, is a major renal compensatory mechanism for the loss of NHE3 and indicate that loss of NHE3 in the kidney alters the set point for Na(+)-fluid volume homeostasis.