About Us

The Pathogenesis of Polycystic Kidney Disease Laboratory studies the pathogenesis of Autosomal Dominant Polycystic Kidney Disease (ADPKD), a common genetic disorder affecting 1 in 800 individuals. The disease is caused by mutations in the PKD1 or the PKD2 genes, which code for polycystin-1 (PC1) and polycystin-2 (PC2), respectively. ADPKD is characterized by the gradual formation and progressive enlargement of fluid-filled cysts, which eventually lead to renal failure.

Currently, there is no treatment for ADPKD other than supportive care and dialysis or kidney transplant becomes necessary when the disease reaches end-stage renal failure. The cystogenetic process is associated with the hyperproliferation of the renal tubular cells, abnormal fluid secretion, and alterations of the extracellular matrix component. To date, the molecular mechanisms underlying normal and cystogenic functions of PC1 remain unclear.

Using a stable PC1 knockdown model that recapitulates the pathological features of ADPKD epithelia, our laboratory showed that cell hyperproliferation is at least in part supported by the increased expression of integrin-β1, an extracellular matrix receptor involved in cell adhesion, migration, cell growth and survival. We observed that PC1 knockdown cells acquire the ability to escape anoikis, an apoptotic pathway triggered by the loss of cell anchorage, though an integrin-β1-dependent mechanism.

Furthermore, our lab provided the first of in vitro and in vivo evidence that ADPKD cells display a significant amplification of centrosomes. The centrosome is an organelle responsible for a variety of essential cellular processes, such as the assembly of primary cilia, cell polarity, trafficking of cytoplasmic organelles, and organization of the mitotic spindle. As such, centrosome duplication occurs only once per cell cycle through a mechanism tightly coupled to the cell cycle progression to ensure that each daughter cell receives only one centrosome. Centrosome amplification due to PC1 knockdown causes genomic instability and aneuploidy, and accounts for the apoptosis and the loss of cell polarity observed in cystic kidney epithelia. These profound alterations of cellular functions may be important triggers of the cystogenic transformation.

Our research is focused on the definition of the molecular pathways that support cell hyperproliferation and the aberrant centrosome duplication. In particular, the objective of one of the ongoing projects is to understand the role of integrin-β1 in the cystogenetic progression triggered by loss of PC1, and to dissect the molecular pathways controlled by integrin-β1 to support cystic cell growth. A second project aims to determining the mechanisms that disrupt centrosome integrity and that contribute to the alteration of the cell cycle progression in PC1 defective cells.