Beschreibung:
<jats:p>Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive renal cystogenesis and other extrarenal manifestations, is one of the most common monogenetic diseases, and is caused by loss of function mutations in <jats:italic>PKD1</jats:italic> and <jats:italic>PKD2</jats:italic>, which encode transmembrane proteins polycystin 1 and 2 (PC1/2). The polycystin proteins have been hypothesized to function as a complex that has been localized to the plasma membrane, cilia, endoplasmic reticulum, and junctions of epithelial cells. The downstream effects of either PC1 or PC2 function loss have not been elucidated. Previously, an investigation of smaller cysts from nephrectomized human ADPKD kidneys revealed a pattern of increased cell width and an altered apical compartment. Subsequently, we observed a decreased abundance and disrupted localization of ezrin, a master scaffold and apical compartment regulator, in similarly characterized cysts. Following this observation, we explored the role of ezrin disruption in a three‐dimensional <jats:italic>in vitro</jats:italic> model of cystogenesis. Acute inactivation of <jats:italic>Pkd2</jats:italic> lead to significant loss of ezrin protein. We confirmed the regulatory relationship between PC2 and ezrin with immunohistochemistry in a genetically inducible <jats:italic>in vivo</jats:italic> short induction model of <jats:italic>Pkd2</jats:italic> inactivation (<jats:italic>Pkd2fl/fl Pax8 rtTA TetOCre</jats:italic>) that revealed a kidney tubule wide decrease in ezrin at the apical membrane. Lipid protein overlay assays and immunoprecipitation experiments demonstrate both PC2 and ezrin interact with similar phosphoinositides, and possibly with each other, suggesting a role for PC2 in apical compartment and junctional assembly. Functionally, we found that PC2 is critical in junctional integrity, with acute inactivation of <jats:italic>Pkd2</jats:italic> causing decreases in transepithelial electrical resistance in inducible primary renal epithelial cells (<jats:italic>Pkd2fl/fl Pax8 rtTA TetOCre</jats:italic>). Ezrin, expressed in all segments of the kidney, is a regulator of many components of the junctions and apical compartment of renal epithelial cells. The disruption of ezrin following inactivation of <jats:italic>Pkd2</jats:italic> in both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> models, and shared interacting lipids, suggests that PC2 may play a role in the regulation of ezrin in renal epithelial cells and that ezrin may be involved in the initiation of cystogenesis following loss of PC2.</jats:p><jats:p><jats:bold>Support or Funding Information</jats:bold></jats:p><jats:p>NIDDK F31 NRSA, PKD Foundation, NIDDK Baltimore Polycystic Kidney Disease Research and Clinical Core Center</jats:p><jats:p>This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in <jats:italic>The FASEB Journal</jats:italic>.</jats:p>