Injury Response Mediated Pathogenesis in Renal Ciliopathies

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PROJECT SUMMARY/ABSTRACT Primary cilia are present on most renal epithelial cells and their disruption leads to cyst formation. Despite their clinical importance, the function of the primary renal cilium remains poorly understood. In previous studies, we and others demonstrated that when cilia assembly (Ift88 mutant) or function (Pkd1 or Pkd2) is disrupted in adult mice, cysts form slowly in focal areas. This occurs despite nearly all epithelial cells in the kidney being mutant for these genes. A hint as to why these cysts develop in focal locations in the adult-induced mutants has emerged from data indicating that renal injury promotes cyst formation and results in cyst formation throughout the kidney. Based on these data, we propose that PKD2 and cilia regulate renal injury and repair responses and that the focal cysts in the adult-induced mutants result from a few cells that have experienced an injury. In the absence of normal cilia function, these cells enter a state of persistent maladaptive repair (as marked by persistent SOX9 expression) and progress to cystogenesis. While cysts are formed in Ift88 and Pkd2 mutants, the cystic kidney phenotype is always more severe with loss of Pkd2. In double mutants, however, the cystic pathology resembles the milder Ift88 mutant alone. Our analysis further shows that the inflammatory response following injury in the Ift88 and Pkd2 mutant mice is altered and as observed with cyst formation; it is exacerbated in Pkd2 mutants compared to Ift88 or Ift88/Pkd2 double mutants. Collectively, these data suggest that IFT88/cilia and PKD2 regulate signaling activities between the ciliated tubule epithelium and the responding non-ciliated immune cells for initiation and resolution of an injury response and that cyst formation is promoted when these signaling pathways are incorrectly controlled. The goals of this proposal are to define the cellular and then molecular mechanism(s) responsible for the focal and widespread injury-induced cyst formation and how IFT88/cilia and PKD2 are involved in this process. From this proposal, we will determine whether cilia loss/dysfunction alters the kidney's sensitivity to injury and results in an increase in the state of epithelial cell maladaptive repair. We will utilize lineage tracing approaches to determine if descendants of injured cells contribute directly to cyst formation. We will define new IFT88/cilia and PKD2-dependent intercellular signaling networks involved in the injury and repair process and how they are dysregulated when cilia are disrupted (Ift88 mutant) or cilia function is perturbed (Pkd2 mutant). Finally, we will define mechanisms by which loss of Ift88 in a Pkd2 mutant background suppresses cyst severity through changes in these injury and repair signaling pathways. The data from the proposal are needed to: 1) elucidate novel functions of the renal cilium, 2) define cellular mechanisms involved in formation of the sporadic and widespread cysts, 3) understand how IFT88/cilia and PKD2 are involved in regulating injury/repair responses, 4) assess how disrupting this injury response promotes cyst formation and expansion, and 5) explore mechanisms involved in the epistatic relationship between Ift88 and Pkd2 mutations.