Pathologic Mechanisms of Polycystic Kidney Disease

University Of New Mexico, Albuquerque NM

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Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the genes encoding polycystin-1 and/or polycystin-2, but results in epithelial cells with disrupted adherensjunctions and compromised beta-catenin signaling pathways. Our data showthe polycystins in a multiprotein complex with adherens junction components. The complexes are associated with plasma membranemicrodomains containing the structural lipid raft protein flotillin-2, but not similar microdomains containing caveolin. Disruption of the adherens junction complexes is linked to down regulation of LAR family receptortyrosine phosphatases and hyperphosphorylation of the proteins in the complex. Since adherens junctions provide structural stability to the epithelial sheet through connections to the actin cytoskeleton, and such connections are compromised in ADPKD, these alterations are likely to contribute to the disease pathology. We hypothesize that flotillin-2 membrane microdomains represent sites wherethe polycystins are activated and cooperate with signaling molecules to bring about stable cell-cell adhesion. Consequently,when polycystin-1 function is mutant or absent, the signaling to initiate cell adhesionis altered and changes in renalcystogenic potential result. The experiments in this proposalwill elucidate the organization and function of the polycystin-containing multiprotein complexes associated with the flotillin-2 membranemicrodomainsby probing for colocalized tyrosine kinases and phosphatases and by monitoringthe contribution of flotillin-2 rafts to actin remodeling, membranetrafficking and stable cell-cell adhesion. Successfulcompletion of the proposed experiments will provide new, mechanistic information on the temporal sequence of eventsleading from polycystin-1activation to the stabilization of E-cadherin mediated adhesion. These mechanistic insights are expected to be useful for designing therapeutic interventions, particularly those that make use of kinase inhibitors.