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• W4220655734 abstract "Since the initial cloning of NHE2 by Orlowski et al and our group, its physiologic role has remained a mystery.1, 2 The study of Seidler, “Sodium/Hydrogen-exchange-2 modulates colonocyte lineage differentiation” published in this issue of Acta Physiologica3 offers the first substantial evidence that its role is an offshoot of its control of intracellular pH to direct epithelial cell differentiation into the absorptive lineage. The initial significance of the cloning of NHE2, which occurred at the same time as the cloning of NHE3, was that it demonstrated that there was a gene family of Na/H exchangers with some members primarily expressed in epithelial cells in a polarized membrane distribution. Initial studies demonstrated that NHE2 was localized to the intestinal brush border, as was NHE3. Functional studies, however, demonstrated that NHE3 was the isoform involved in apical membrane Na+ uptake in the intestine and kidney.4, 5 In parallel to studies of NHE3, attempts to define the role of NHE2 in physiology and pathophysiology not only demonstrated that it was not necessary for intestinal or renal Na absorption,6 but also, whilst small contributions to multiple processes were identified, in no mammalian system was NHE2 clearly the major contributor. Studied most extensively using mouse KO models, NHE2 null mice did not develop diarrhoea, had no changes in quantitated intestinal Na+ absorption, and double KO of NHE3 and NHE2 were not significantly different than the NHE3 KO alone in diarrhoea, intestinal Na+ absorption, or reduced life expectancy.6, 7 It was observed, however, that in the rabbit colon, NHE2 and NHE3 made approximately equal contributions to Na+ absorption and in the rat colon, some studies indicated a major role for NHE2 in Na+ absorption.8, 9 Other functional studies did indicate a role for NHE2, but no mechanisms were described. For instance, conventional NHE2 KO mice developed reduced H+ secretion at weaning and had absent H+ secretion as adult mice. This was associated with gastritis with mucosal atrophy, reduced number of parietal and Chief cells.10, 11 NHE2 null mice also exhibited reduced recovery from laser-induced ulceration of the stomach.12 Whilst a functional role for NHE2 has been elusive, multiple differences between it and other epithelial NHEs have been identified. The plasma membrane NHEs have similar turnover numbers13; however, NHE2 has a short half-life (~3 hours) compared to other plasma membrane NHEs, NHE1 (24 hours) and NHE3 (14 hours).14 Whilst NHE3 is regulated acutely by changes in its rates of endocytosis and exocytosis, regulation of NHE2 does not appear to involve changes in plasma membrane trafficking, although there is some contradictory data in this area. Most dramatically, however, is a difference in pH sensitivity of NHE2, with increased cooperativity of the two H+ sites, resulting in increased activity in an intracellular alkaline environment with continued activity at alkaline pHs that inhibit the other plasma membrane NHEs, as well as increased sensitivity to inhibition by acidic pH.15 An important observation that set the stage for the current study was the observation by Seidler, Shull, and Montrose, that NHE2 was the major apical Na/H exchanger in mouse distal colonic crypt.16, 17 Building on this observation, the current study used conventional NHE2 KO mouse mid distal colon and Caco-2 cells in which intracellular pH was modified by altering the external pH. Findings/Conclusions made from the current study: 1. Using isolated crypts, an increasing acidic pH gradient of approximately 0.3 pH units from crypt mouth to crypt base in wild type mice was demonstrated. High crypt expression of NHE2 in mouse mid colon crypt but not crypt base stem cells was confirmed, with NHERF2 KO crypts having further acidification (by 0.1-0.3 pH units) of the non-crypt base or crypt mouth epithelial population. 2. A small contribution of NHE2 to colonic Na+ absorption was demonstrated. 3. In NHE2 KO: (a) There were elongated crypts in which were distributed the same number of proliferating cells, although there was also some evidence of reduced proliferation rates in colonoids made from NHE2 null colons. (b) There was a change in the differentiation programme, with a reduction of multiple components of the absorptive enterocyte pathways and increased components of the secretory pathways. 4. In Caco-2 cells in which intracellular pH was modified by altering the external bathing solutions, there was: (a) reduced rate of proliferation; (b) acidification duplicated the NHE2 KO in the colon by reducing epithelial markers of absorptive enterocytes including NHE3, DRA, sucrase-isomaltase (SI), but there was no change in NHE2 expression; (c) alkalinization increased expression of NHE3, DRA, SI, again without altering NHE2 message. The major conclusion from this study was that expression of NHE2 in the colonic crypt normally causes intracellular alkalinization of the crypt, which alters the differentiation program and leads to stimulation of the absorptive enterocyte pathway at the expense of the secretory pathway. The possibility was left open that it is another function of NHE2 that causes this effect on differentiation. The property of NHE2 thought to allow it to function in this way is its high H+ affinity with activity in a more alkaline pH range than other plasma membrane NHEs. While questions of mechanisms and to some extent the physiologic relevance of the role of intestinal NHE2 remain to be defined, these studies provide the most convincing evidence yet proposed for the physiologic and potentially pathophysiologic role for intestinal NHE2. This study is a welcome step forward in understanding the role of NHE2. The authors have declared no conflict of interest." @default.
• W4220655734 created "2022-04-03" @default.
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• W4220655734 date "2022-02-11" @default.
• W4220655734 modified "2023-10-16" @default.
• W4220655734 title "Has a Physiologic Function for NHE2 Finally been Identified?" @default.
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• W4220655734 doi "https://doi.org/10.1111/apha.13792" @default.
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