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1 Department of Molecular Genetics, Biochemistry, and Microbiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
2 Department of Molecular and Cellular Physiology, The University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
3 Department of Biological Sciences, Northern Kentucky University, Highland Heights, Kentucky, USA
* To whom correspondence should be addressed. E-mail: shullge{at}ucmail.uc.edu.
The degree to which loss of the NHE3 Na+/H+ exchanger in kidney contributes to impaired Na+-fluid volume homeostasis in NHE3-deficient (Nhe3-/-) mice is unclear because of the co-existing 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.
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