Intestinal NaCl transport in NHE2 and NHE3 knockout mice

Abstract

Sodium/proton exchangers [Na(+)/H(+) (NHEs)] play an important role in salt and water absorption from the intestinal tract. To investigate the contribution of the apical membrane NHEs, NHE2 and NHE3, to electroneutral NaCl absorption, we measured radioisotopic Na(+) and Cl(-) flux across isolated jejuna from wild-type [NHE(+)], NHE2 knockout [NHE2(-)], and NHE3 knockout [NHE3(-)] mice. Under basal conditions, NHE(+) and NHE2(-) jejuna had similar rates of net Na(+) (approximately 6 microeq/cm(2) x h) and Cl(-) (approximately 3 microeq/cm(2) x h) absorption. In contrast, NHE3(-) jejuna had reduced net Na(+) absorption (approximately 2 microeq/cm(2) x h) but absorbed Cl(-) at rates similar to NHE(+) and NHE2(-) jejuna. Treatment with 100 microM 5-(N-ethyl-N-isopropyl) amiloride (EIPA) completely inhibited net Na(+) and Cl(-) absorption in all genotypes. Studies of the Na(+) absorptive flux (J) indicated that J in NHE(+) jejunum was not sensitive to 1 microM EIPA, whereas J in NHE3(-) jejunum was equally sensitive to 1 and 100 microM EIPA. Treatment with forskolin/IBMX to increase intracellular cAMP (cAMP(i)) abolished net NaCl absorption and stimulated electrogenic Cl(-) secretion in all three genotypes. Quantitative RT-PCR of epithelia from NHE2(-) and NHE3(-) jejuna did not reveal differences in mRNA expression of NHE3 and NHE2, respectively, when compared with jejunal epithelia from NHE(+) siblings. We conclude that 1) NHE3 is the dominant NHE involved in small intestinal Na(+) absorption; 2) an amiloride-sensitive Na(+) transporter partially compensates for Na(+) absorption in NHE3(-) jejunum; 3) cAMP(i) stimulation abolishes net Na(+) absorption in NHE(+), NHE2(-), and NHE3(-) jejunum; and 4) electroneutral Cl(-) absorption is not directly dependent on either NHE2 or NHE3.

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

“…In addition the presence of NHE2 and NHE3 on the apical membrane of colonic epithelial cells has been confirmed [20]. NHE3 knock out mice develope diarrhoea, which supports the idea that this might be the dominant NHE isoform, responsible for Na + uptake in the intestine [12,35,49]. Together with NHE3, the SLC26A3 Cl -/HCO 3 -exchanger (or downregulated in adenoma; DRA), a member of the SLC26 gene family, maintains the absorption of NaCl in the colon.…”

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

“…Interferon-γ and TNF-α decrease NHE3 activity causing diarrhea [51,145,2]. Consistent with a role in inflammatory bowel disease, NHE3 expression and/or activity is decreased in mouse models and human disease [159,187] .…”

“…Ultimately, despite significant expression and activity in both bowel and kidney, it appears that the absence of NHE2 can be compensated for. It is likely that NHE3 and NHE8 perform these compensatory roles, at least under some circumstances [6,51,69]. Perhaps not surprising, given the relatively benign phenotype for NHE2 KO mice, there is no known human disease ascribed to defects in this transporter [110].…”

Gut hormones and gut microbiota: implications for kidney function and hypertension

“…45 Indeed, NHE3-knockout mice show lower BP compared with wildtype mice. 46 Thus, blockade of intestinal NHE3 to reduce intestinal sodium absorption could be a potentially novel strategy for treatment of hypertension 47 as is the case with commonly used diuretics which block renal tubular reabsorption of sodium. Animal studies have shown that by inhibiting intestinal NHE3-mediated sodium absorption, SAR218034 can serve as a new class of antihypertensive drugs.…”