Restoration of Na+/H+ exchanger NHE3-containing macrocomplexes ameliorates diabetes-associated fluid loss

The Journal of Clinical Investigation
Peijian HeC Chris Yun


Diarrhea is one of the troublesome complications of diabetes, and the underlying causes of this problem are complex. Here, we investigated whether altered electrolyte transport contributes to diabetic diarrhea. We found that the expression of Na+/H+ exchanger NHE3 and several scaffold proteins, including NHE3 regulatory factors (NHERFs), inositol trisphosphate (IP₃) receptor-binding protein released with IP₃ (IRBIT), and ezrin, was decreased in the intestinal brush border membrane (BBM) of mice with streptozotocin-induced diabetes. Treatment of diabetic mice with insulin restored intestinal NHE3 activity and fluid absorption. Molecular analysis revealed that NHE3, NHERF1, IRBIT, and ezrin form macrocomplexes, which are perturbed under diabetic conditions, and insulin administration reconstituted these macrocomplexes and restored NHE3 expression in the BBM. Silencing of NHERF1 or IRBIT prevented NHE3 trafficking to the BBM and insulin-dependent NHE3 activation. IRBIT facilitated the interaction of NHE3 with NHERF1 via protein kinase D2-dependent phosphorylation. Insulin stimulated ezrin phosphorylation, which enhanced the interaction of ezrin with NHERF1, IRBIT, and NHE3. Additionally, oral administration of lysophosphatidic aci...Continue Reading


Feb 1, 1990·Archives of Internal Medicine·K I Ogbonnaya, R Arem
Feb 1, 1985·Annals of Internal Medicine·R N FedorakE B Chang
Apr 1, 1997·Proceedings of the National Academy of Sciences of the United States of America·C H YunMark Donowitz
Jul 14, 1998·Nature Genetics·P J SchultheisG E Shull
Oct 9, 1999·The Journal of Biological Chemistry·K KurashimaS Grinstein
Jun 9, 2000·Annual Review of Physiology·K E Barrett, S J Keely
Jun 8, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·U ChristenM G von Herrath
Jun 27, 2001·Free Radical Biology & Medicine·N E CameronM A Cotter
Aug 9, 2002·American Journal of Physiology. Renal Physiology·Jelena KlisicPatrice M Ambühl
Aug 10, 2002·Proceedings of the National Academy of Sciences of the United States of America·Shirish ShenolikarEdward J Weinman
Apr 3, 2003·The Journal of Clinical Investigation·Michael Field
Sep 5, 2003·American Journal of Physiology. Cell Physiology·Whaseon Lee-KwonMark Donowitz
Jun 16, 2004·Proceedings of the National Academy of Sciences of the United States of America·Huiren ZhaoJerrold R Turner
Feb 16, 2005·Annual Review of Physiology·Nicholas C ZachosMark Donowitz
Mar 25, 2005·Biochemical Society Transactions·R V FareseM L Standaert
May 13, 2005·American Journal of Physiology. Cell Physiology·Dongsheng WangC Chris Yun
Jul 9, 2005·The Journal of Pharmacology and Experimental Therapeutics·A FarhadiA Banan
Jun 14, 2006·Proceedings of the National Academy of Sciences of the United States of America·Kyoko ShirakabeKatsuhiko Mikoshiba
Oct 4, 2006·The Journal of Clinical Investigation·Daniel R ClayburghJerrold R Turner
Oct 5, 2006·American Journal of Physiology. Renal Physiology·Daniel G FusterOrson W Moe
Mar 10, 2007·Pflügers Archiv : European journal of physiology·Jutta HillesheimUrsula Seidler
Apr 27, 2007·Progress in Lipid Research·Laurens A van Meeteren, Wouter H Moolenaar
Aug 4, 2007·Kidney International. Supplement·H Noh, George L King
Sep 12, 2007·Journal of Proteome Research·Mark DonowitzXuhang Li
Oct 10, 2007·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Kyungmoo YeaSung Ho Ryu
May 16, 2008·American Journal of Physiology. Cell Physiology·Lixin ZhuJohn G Forte
Jun 23, 2009·Annals of the New York Academy of Sciences·Ursula SeidlerBrigitte Riederer
Sep 22, 2009·Current Gastroenterology Reports·Milena Gould, Joseph H Sellin
May 1, 2010·Circulation Research·Pedro Geraldes, George L King
Oct 14, 2010·Neurogastroenterology and Motility : the Official Journal of the European Gastrointestinal Motility Society·B ChandrasekharanS Srinivasan


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Jun 10, 2016·American Journal of Physiology. Renal Physiology·Peijian HeC Chris Yun
May 25, 2018·American Journal of Physiology. Gastrointestinal and Liver Physiology·Kayte A JenkinC Chris Yun
Nov 14, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Luqing ZhaoPeijian He
Nov 28, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Songbai LinC Chris Yun
May 21, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Balasubramanian PalaniappanUma Sundaram
Mar 30, 2017·Proceedings of the National Academy of Sciences of the United States of America·Katsuhiro KawaaiKatsuhiko Mikoshiba
Dec 15, 2020·Pharmacology & Therapeutics·Jaana van GastelStuart Maudsley

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