Friday, April 19, 2024
4/19/2024
Project Abstract Cystic kidney diseases affect 1:500 people and account for 5-10% of all patients with end stage renal disease representing a significant health care burden. This spectrum of disorders is caused by mutations in proteins required for cilia formation (Intraflagellar transport protein 88, Ift88) or function (Polycystin 1, Pkd1; Polycsytin 2, Pkd2). In addition, patients with these disorders experience periods of slow focal cyst formation and rapid, severe cyst progression. Data from mouse models indicate that loss of cilia related proteins (Ift88, Pkd1, Pkd2) results in slow focal cyst formation suggesting that additional environmental factors are required for rapid cystogenesis often observed in human patients. This hypothesis is supported by data from multiple labs, including our own, indicating that renal injury promotes rapid cystogenesis in mice with cilia dysfunction. Importantly, renal injury promotes the accumulation of immune cells in wild type mice. Data from our lab and others indicate that immune cell accumulation is further enhanced and prolonged in mice with cilia dysfunction suggesting that persistent immune cell accumulation may be the cause of rapid cyst formation following injury in mice with cilia dysfunction. However, the type of immune cell that promotes cystic disease following injury is poorly understood and represents a gap in knowledge. The preliminary data outlined in this application show that genetic deletion of all adaptive immune cells (CD4 T cells, CD8 T cells, and B cells) or pharmacological depletion of just CD4 T cells reduces cyst severity following injury in mice with cilia dysfunction suggesting that CD4 T cells may be the critical link between renal injury and rapid cystogenesis. To identify the subtype of CD4 T cell important in this process, we performed flow cytometry analysis of control and cilia mutant kidneys at various time points following injury. Our preliminary data indicate that mice with cilia dysfunction have increased and persistent accumulation of CD4+ Foxp3+ T regulatory cells (Tregs). These data led to the overall hypothesis that increased and persistent accumulation of Tregs following injury causes prolonged and abnormal epithelial proliferation and rapid cyst expansion in mice with cilia dysfunction. The goal of this application is to identify the mechanistic link between rapid cystogenesis and T regulatory cells. Our hypotheses will be tested with the following specific aims: 1. To test the hypothesis that cilia dysfunction causes persistent and/or enhanced accumulation of Tregs in regions adjacent to expanding cysts following renal injury. 2. To test the hypothesis that Tregs promote injury induced cyst expansion in conditional Ift88 mice through secretion of IL-10, a cytokine that is predominantly produced by Tregs and has previously been reported to drive cystic epithelial cell proliferation. Data collected from this proposal will be used to develop novel immune cell modulating drugs that affect Treg number and function (ability to produce IL-10) in patients with rapidly progressive cystic kidney disease.
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