Renal function in NHE3-deficient mice with transgenic rescue of small intestinal absorptive defect.
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.
Woo
Alison L
AL
Department of Molecular Genetics, Biochemistry, and Microbiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
Noonan
William T
WT
Schultheis
Patrick J
PJ
Neumann
Jonathan C
JC
Manning
Patrice A
PA
Lorenz
John N
JN
Shull
Gary E
GE
D000450:Aldosterone / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015152:Blotting, Northern; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004039:Diet, Sodium-Restricted; D005110:Extracellular Space / Q000502:physiology; D005919:Glomerular Filtration Rate; D006339:Heart Rate / Q000502:physiology; D007022:Hypotension / Q000503:physiopathology; D007408:Intestinal Absorption / Q000235:genetics* / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D012079:Renal Circulation / Q000502:physiology; D012964:Sodium / Q000494:pharmacology; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; C000613386:Slc9a3 protein, mouse; C000613387:Slc9a3 protein, rat; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000450:Aldosterone; D012313:RNA; D012964:Sodium