title: Mice lacking the Na+/H+ exchanger 2 have impaired recovery of intestinal barrier function.
abstract: Ischemic injury induces breakdown of the intestinal barrier. Recent studies in porcine postischemic tissues indicate that inhibition of NHE2 results in enhanced recovery of barrier function in vitro via a process involving interepithelial tight junctions. To further study this process, recovery of barrier function was assessed in wild-type (NHE2(+/+)) and NHE2(-/-) mice in vivo and wild-type mice in vitro. Mice were subjected to complete mesenteric ischemia in vivo, after which barrier function was measured by blood-to-lumen mannitol clearance over a 3-h recovery period or measurement of transepithelial electrical resistance (TER) in Ussing chambers immediately following ischemia. Tissues were assessed for expression of select junctional proteins. Compared with NHE2(+/+) mice, NHE2(-/-) mice had greater intestinal permeability during the postischemic recovery process. In contrast to prior porcine studies, pharmacological inhibition of NHE2 in postischemic tissues from wild-type mice also resulted in significant reductions in TER. Mucosa from NHE2(-/-) mice displayed a shift of occludin and claudin-1 expression to the Triton-X-soluble membrane fractions and showed disruption of occludin and claudin-1 localization patterns following injury. This was qualitatively and quantitatively recovered in NHE2(+/+) mice compared with NHE2(-/-) mice by the end of the 3-h recovery period. Serine phosphorylation of occludin and claudin-1 was downregulated in NHE2(-/-) postischemia compared with wild-type mice. These data indicate an important role for NHE2 in recovery of barrier function in mice via a mechanism involving tight junctions.
authors: Department of Population Health, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606, USA.
authors: Adam J
authors: AJ
authors: Moeser
authors: Prashant K
authors: PK
authors: Nighot
authors: Kathleen A
authors: KA
authors: Ryan
authors: Janet E
authors: JE
authors: Simpson
authors: Lane L
authors: LL
authors: Clarke
authors: Anthony T
authors: AT
authors: Blikslager
mesh_terms: D000818:Animals; D062445:Claudin-1; D007413:Intestinal Mucosa / Q000503:physiopathology*; D007421:Intestine, Small / Q000098:blood supply; D007511:Ischemia / Q000503:physiopathology; D008353:Mannitol / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin; D010539:Permeability; D010766:Phosphorylation; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000502:physiology*; D019108:Tight Junctions / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D062445:Claudin-1; C568113:Cldn1 protein, mouse; D008565:Membrane Proteins; D062793:Occludin; C568986:Ocln protein, mouse; C513111:Slc9a2 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D008353:Mannitol