Basic—Alimentary TractLysophosphatidic Acid Stimulates the Intestinal Brush Border Na+/H+ Exchanger 3 and Fluid Absorption via LPA5 and NHERF2
Section snippets
Animals
Lpa2−/− mice in C57BL/6 background were reported recently.13Nherf2−/− mice10 were bred in C57BL/6 or FVB/N background for at least 15 generations. Nherf2−/− mice on C57BL/6 background were compared with Lpa2−/− mice, and Nherf2−/− mice on the FVB/N background were compared with mice deficient for other NHERF proteins.10 Age- and sex-matched littermates of the same respective genetic background were used as controls. It was made certain that both genetic backgrounds responded similarly to LPA (
LPA Induces NHE3-Dependent Water Absorption In Vivo
We sought to test whether LPA can regulate NHE3-dependent intestinal fluid absorption, which is the hallmark of diarrhea. We adapted the in vivo perfusion system in which a small loop of intestine of an anesthetized mouse is perfused in a recirculating manner.15Figure 1A depicts typical changes in fluid absorption over 3 hours. There was a net absorption of fluid in the ileum at the rate of 50.6 ± 3.7 μL/cm/h at basal conditions (Figure 1B). To determine the effect of LPA, 20 μM LPA was
Discussion
In the present study, we investigated the effect of LPA on NHE3 activity and NHE3-mediated fluid absorption in the intestine. We found that LPA is a potent stimulator of Na+ and fluid absorption. The presence of LPA is able to overcome diarrhea induced by CT or TNF-α, suggesting its potential therapeutic usage. LPA specifically acted on NHE3, but not on NHE1 or NHE2. Moreover, this regulation was dependent on the presence of NHERF2 as demonstrated both in vitro and in vivo. Our study identifies
Acknowledgments
Drs Lin and Yeruva contributed equally to this work.
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Conflicts of interest The authors disclose no conflicts.
Funding This work was funded by National Institutes of Health grants DK061416 (CCY), MH51699 and HD50685 (JC) and by DFGSFB621-C9 (US). SL was supported by the Crohn's and Colitis Foundation of America. PH was supported by the American Heart Association. AS and MC were supported by postdoctoral stipends of the Hannover biomedical Research School that were funded by the DAAD and Abbot GmbH via the “matching fund” program. We thank the Emory Digestive Disease Research Development Center (supported by DK064399) for the use of light microscope and the Zeiss 510 confocal microscope and the Volkswagen Stiftung for funding of the Leica LSM.