Evidence for a causal link between adaptor protein PDZK1 downregulation and Na⁺/H⁺ exchanger NHE3 dysfunction in human and murine colitis.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Singh, Anurag Kumar
MetadataShow full item record
AbstractA dysfunction of the Na(+)/H(+) exchanger isoform 3 (NHE3) significantly contributes to the reduced salt absorptive capacity of the inflamed intestine. We previously reported a strong decrease in the NHERF family member PDZK1 (NHERF3), which binds to NHE3 and regulates its function in a mouse model of colitis. The present study investigates whether a causal relationship exists between the decreased PDZK1 expression and the NHE3 dysfunction in human and murine intestinal inflammation. Biopsies from the colon of patients with ulcerative colitis, murine inflamed ileal and colonic mucosa, NHE3-transfected Caco-2BBe colonic cells with short hairpin RNA (shRNA) knockdown of PDZK1, and Pdzk1-gene-deleted mice were studied. PDZK1 mRNA and protein expression was strongly decreased in inflamed human and murine intestinal tissue as compared to inactive disease or control tissue, whereas that of NHE3 or NHERF1 was not. Inflamed human and murine intestinal tissues displayed correct brush border localization of NHE3 but reduced acid-activated NHE3 transport activity. A similar NHE3 transport defect was observed when PDZK1 protein content was decreased by shRNA knockdown in Caco-2BBe cells or when enterocyte PDZK1 protein content was decreased to similar levels as found in inflamed mucosa by heterozygote breeding of Pdzk1-gene-deleted and WT mice. We conclude that a decrease in PDZK1 expression, whether induced by inflammation, shRNA-mediated knockdown, or heterozygous breeding, is associated with a decreased NHE3 transport rate in human and murine enterocytes. We therefore hypothesize that inflammation-induced loss of PDZK1 expression may contribute to the NHE3 dysfunction observed in the inflamed intestine.
CitationEvidence for a causal link between adaptor protein PDZK1 downregulation and Na⁺/H⁺ exchanger NHE3 dysfunction in human and murine colitis. 2015, 467 (8):1795-807 Pflugers Arch.
The following license files are associated with this item:
- Preserved Na(+)/H(+) exchanger isoform 3 expression and localization, but decreased NHE3 function indicate regulatory sodium transport defect in ulcerative colitis.
- Authors: Yeruva S, Farkas K, Hubricht J, Rode K, Riederer B, Bachmann O, Cinar A, Rakonczay Z, Molnár T, Nagy F, Wedemeyer J, Manns M, Raddatz D, Musch MW, Chang EB, Hegyi P, Seidler U
- Issue date: 2010 Jul
- Downregulation of the NHE3-binding PDZ-adaptor protein PDZK1 expression during cytokine-induced inflammation in interleukin-10-deficient mice.
- Authors: Lenzen H, Lünnemann M, Bleich A, Manns MP, Seidler U, Jörns A
- Issue date: 2012
- Down regulation of small intestinal ion transport in PDZK1- (CAP70/NHERF3) deficient mice.
- Authors: Hillesheim J, Riederer B, Tuo B, Chen M, Manns M, Biber J, Yun C, Kocher O, Seidler U
- Issue date: 2007 Jul
- NHERF3 (PDZK1) contributes to basal and calcium inhibition of NHE3 activity in Caco-2BBe cells.
- Authors: Zachos NC, Li X, Kovbasnjuk O, Hogema B, Sarker R, Lee LJ, Li M, de Jonge H, Donowitz M
- Issue date: 2009 Aug 28
- Differential association of the Na+/H+ Exchanger Regulatory Factor (NHERF) family of adaptor proteins with the raft- and the non-raft brush border membrane fractions of NHE3.
- Authors: Sultan A, Luo M, Yu Q, Riederer B, Xia W, Chen M, Lissner S, Gessner JE, Donowitz M, Yun CC, deJonge H, Lamprecht G, Seidler U
- Issue date: 2013