title: Ezrin distribution is abnormal in principal cells from a murine model of autosomal recessive polycystic kidney disease.
abstract: Abnormalities in cell proliferation and intracellular signaling are features of inherited human and murine polycystic kidney diseases (PKD), regardless of the primary genetic defects. Loss of protein kinase A regulation of cell proliferation has been reported in the murine C57BL/6JCys1cpk-/- (cpk) model of autosomal recessive PKD. Qualitative differences in protein kinase A subunit distribution were observed between filter-grown cultures of noncystic- (C57BL/6J mice) and cystic cpk-derived principal cells. It was hypothesized that protein kinase A subunit distribution differences were mediated by differences in A-kinase anchoring protein (AKAP) expression, so expression of four AKAPs was examined in filter-grown cultures of primary murine cystic- and noncystic-derived principal cells. AKAP-KL expression was ambiguous, but mAKAP, AKAP95, and ezrin were expressed at expected molecular sizes and cellular locations in noncystic-derived cells. Perinuclear mAKAP and nuclear AKAP95 were distributed normally in cpk-derived cells. Expression of AKAP95 in cystic epithelium was diminished relative to controls, and ezrin expression was modestly decreased and abnormally distributed within a region near the apical surface. Qualitative differences were observed in ezrin location in response to medium change or stimulation with epidermal growth factor which suggested cell-specific differences may result from the cpk mutation or the abnormal epidermal growth factor receptor phenotype that characterizes PKD. Ezrin has been implicated in tubulogenesis, so altered ezrin expression or function could be disruptive. If PKD mutations that contribute to PKD pathogenesis are postulated to disrupt normal tubular development, perhaps the mechanism includes altered ezrin function and abnormal protein kinase A targeting.
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine and the Rainbow Center for Childhood PKD, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland, Research Institute, OH 44106-6003, USA. sao3@po.cwru.edu
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Orellana
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Quinoñes
authors.forename: Marylou L
authors.initials: ML
authors.lastname: Mandapat
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000378:metabolism*; D017044:Polycystic Kidney, Autosomal Recessive / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D010750:Phosphoproteins; D000099149:Ezrin