Intestinal epithelial‐specific NHE3 knockout causes metabolic acidosis

Abstract

The Na+/H+ exchanger isoform 3 (NHE3) has an important role in intestinal and renal Na+ uptake and acid‐base regulation. While renal‐specific NHE3 knockout models have been successfully generated, no intestinal‐specific model has been described. Of note, renal‐specific NHE3 knockout does not result in altered blood pH or bicarbonate levels (Kidney International; 2017, 92:397–414) and conventional intestinal epithelial cell‐specific NHE3 knockout mice die shortly after birth. To determine the role of NHE3 selectively in the intestine, we generated tamoxifen (Tam)‐inducible epithelial‐specific NHE3 knockout mice (NHE3IEC‐KO) by intercrossing NHE3loxlox (control, Con) and VillinCreERT2 mice. Semiquantitative fluorescent labeling determined that application of Tam (5 days, 200 mg/kg via oral gavage) deleted NHE3 from the small intestine and colon of NHE3IEC‐KO mice, whereas labeling in the proximal tubule and thick ascending limb of the kidney was unaffected. Before Tam, Con and NHE3IEC‐KO (n=8 and 4, respectively) mice had comparable blood pH (7.4±0.01 vs 7.4±0.01), HCO3− (24.7±0.7 vs 24.6±0.6 mM), base excess (0.5±0.2 vs 0.6±0.1 mM) and Na+ concentrations (147±0.4 vs 148±0.8 mM). Two weeks after Tam, compared to Con mice, NHE3IEC‐KO mice show significant metabolic acidosis (Δ change: 0±0.01 vs −0.15±0.03, P<0.05), lower HCO3− (Δ change: 0±0.4 vs −7±1, P<0.05) and negative base excess (Δ change: 0±0.7 vs −9±2, P<0.05), whereas plasma Na+ was unaffected (Δ change: 0.5±0.6 vs −0.3±1, NS). Indirect evidence for impaired intestinal HCO3− uptake using intestinal flushes showed a significantly higher flush pH in NHE3IEC‐KO compared to Con mice (7.9±0.1 vs 7.4±0.1, P<0.05). In conclusion, we successfully generated intestinal epithelial cell‐specific NHE3 knockout mice. The mouse model will be useful to study different aspects of NHE3 in the intestine and colon. The data indicate a prominent unrecognized role of the intestine for acid‐base regulation.Support or Funding InformationNovo Nordisk Foundation, the Lundbeck Foundation, Danish Medical Research Council, NIH 1R01DK110621, APS STRIDE Undergraduate Summer Research Fellowship 1R25HL115473‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.