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(-/-) (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.

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…Given the large amount of sodium and water which is not reabsorbed from the proximal tubule in the absence of NHE3 it is surprising the NHE3 KO mice survive at all. This is best explained by the large decrease in GFR observed in these animals, which is mediated by increased sodium delivery to the macula densa [114,176].…”

Renal Vacuolar H+-ATPase

“…About 50% of overall apical NHE activity may be mediated by NHE-3, the remainder by another isoform(s) (111). Genetic knock-out of NHE-2 has no effect on renal function, whereas complete or kidney-specific knock-out of NHE-3 results in a reduction of proximal tubular bicarbonate reabsorption (555) as well as Na ϩ and water loss (451,573). Up to 40% of proximal tubule bicarbonate reabsorption is Na ϩ independent and is sensitive to the vacuolar H ϩ -ATPase inhibitor bafilomycin (103,555), and it has thus been postulated to be mediated by vacuolar H ϩ -ATPases expressed in the brush-border membrane.…”

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

“…Transgenic mice in which the intestinal fatty acid binding protein (IFABP) promoter was used to drive expression of NHE3 in the small intestine (16) were obtained from an established colony. These IFABP/NHE3 transgenic mice were backcrossed for two to three generations with Nhe3 ϩ/Ϫ mice, also from an established colony (15), to produce Nhe3 ϩ/ϩ and Nhe3 Ϫ/Ϫ mice harboring the IFABP/ NHE3 transgene (tgNhe3 ϩ/ϩ and tgNhe3 Ϫ/Ϫ ).…”

“…To assess these issues, we developed a transgenic mouse in which NHE3 is expressed in the small intestine via the intestinal fatty acid binding protein (IFABP) promoter and crossed it with Nhe3 Ϫ/Ϫ mice (16). Both dietary Na ϩ restriction and Na ϩ loading were better tolerated in transgenic Nhe3 Ϫ/Ϫ (tgNhe3 Ϫ/Ϫ ) mice than in nontransgenic Nhe3 Ϫ/Ϫ mice (ntg Nhe3 Ϫ/Ϫ ), and salt loading led to a substantial reduction of aldosterone levels in tgNhe3 Ϫ/Ϫ mice, indicating a partial correction of the extracellular fluid-volume deficit.…”