Sunday, April 27, 2025
4/27/2025
CDKN1A (p21) regulation of cyst growth - Mutations disrupting cilia function (Pkd1 or Pkd2) cause renal cyst formation. The relationship between cilia, the Pkd proteins (polycystins) and cytogenesis is poorly understood. Induction of Pkd1 and Pkd2 gene loss in adult mice causes focal cyst initiation, despite the genes being efficiently deleted from nearly all the cells in the kidney. It was proposed that an additional insult may be required for cystogenesis to occur. Multiple groups have now reported that the number of cysts and the cyst expansion rate is accelerated by renal injury. This led to the hypothesis that polycystins regulate an injury and repair process. In the absence of polycystins, cells that experience an injury are unable to repair adequately leading to maladaptive repair conditions. We predict these maladaptive-repair cells contribute to the focal cysts in adult mutants and to the rapidly forming, widespread cysts induced by injury. This is further supported by gene expression analyses revealing that a subpopulation of epithelial cells in pre-cystic mutants have elevated expression of genes induced by renal injury. One gene we found to be aberrantly expressed prior to cyst initiation in the Pkd1 and Pkd2 mutants and following injury is CDKN1A (p21), a protein involved in cell cycle inhibition and maintenance of epithelia cell differentiation. In normal kidney epithelia, p21 is not readily detectable, but is induced rapidly by injury to prevent injured cells from proliferating until repair is complete. p21 down regulation then allows the cell to progress through the cell cycle to complete tissue repair. Unexpectedly, the number of p21 expressing cells was greatly increased in Pkd2 mutants , despite cystic kidney disease being considered a proliferative disorder. Our data are in direct contrast to findings from nearly 20 years ago showing that Pkd1 and Pkd2 function through the Jak/Stat pathway to induce p21 expression. One goal of this project is to directly address this controversy by defining the relationship between p21 expression and cyst development and severity in Pkd1 and Pkd2 mutants. We will determine whether is abnormally regulated as part of an altered injury response in the mutants. Our studies will determine whether cells expressing p21 display cellular characteristics and transcriptional changes linked to cyst development. We will trace the fate of cells that express or had expressed p21 to determine if they contribute to cysts. Finally, using innovative mouse models where we can sustain or repress p21 expression at defined stages of cystogenesis, we will directly test the importance of p21 in cyst initiation and expansion. Collectively, our data will provide a detailed understanding of p21’s role in cystic disease. As such, the data will pave the way for innovative strategies to manage PKD more effectively, potentially leading to improved treatment options and better outcomes for PKD patients.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).