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

Abstract

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 −/− (tg Nhe3 −/−) mice tolerated dietary NaCl depletion better than nontransgenic knockouts and showed no evidence of renal salt wasting. Unlike nontransgenic Nhe3 −/− mice, tg Nhe3 −/− mice tolerated a 5% NaCl diet. When fed a 5% NaCl diet, tg Nhe3 −/− mice had lower serum aldosterone than tg Nhe3 −/− mice on a 1% NaCl diet, indicating improved extracellular fluid volume status. Na+-loaded tg Nhe3 −/− 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.