Loss of polycystins suppresses deciliation via the activation of the centrosomal integrity pathway

The primary cilium is a microtubule-based, antenna-like organelle housing several signaling pathways. It follows a cyclic pattern of assembly and deciliation (disassembly and/or shedding), as cells exit and re-enter the cell cycle, respectively. In general, primary cilia loss leads to kidney cystogenesis. However, in animal models of autosomal dominant polycystic kidney disease, a major disease caused by mutations in the polycystin genes (Pkd1 or Pkd2), primary cilia ablation or acceleration of deciliation suppresses cystic growth, whereas deceleration of deciliation enhances cystogenesis. Here, we show that deciliation is delayed in the cystic epithelium of a mouse model of postnatal deletion of Pkd1 and in Pkd1- or Pkd2-null cells in culture. Mechanistic experiments show that PKD1 depletion activates the centrosomal integrity/mitotic surveillance pathway involving 53BP1, USP28, and p53 leading to a delay in deciliation. Reduced deciliation rate causes prolonged activation of cilia-based signaling pathways that could promote cystic growth. Our study links polycystins to cilia dynamics, identifies cellular deciliation downstream of the centrosomal integrity pathway, and helps explain pro-cystic effects of primary cilia in autosomal dominant polycystic kidney disease.

JAK2 is highly expressed by cyst-lining cells and regulates cystogenesis

ABSTRACTDysregulated JAK/STAT signalling is implicated in polycystic kidney disease, which is a common genetic disease leading to renal failure. However, the mechanisms underlying JAK/STAT-mediated cystogenesis arepoorlyunderstood.TheroleofJAK2wasinvestigated immunohistochemically in a murine model of cystic disease (Pkd1nl/nl). In the normal kidney, JAK2 is restricted to tubular epithelial and vascular cells with lesser staining in bowman’s capsule and is undetectable in the interstitium. By contrast, in the diseased kidney JAK2 appears stronger in cyst-lining cells when compared to normal tubules and appears mislocalised in the interstitium. Given that JAK2 is a major tyrosine kinase activating JAK/STAT, we considered whether its inhibition can attenuate cystic growth in vitro. To assess this we used curcumin, a natural phytochemical, which significantly reduced JAK2 levels and STAT3 activity. Consistently, reduced JAK2/STAT3 activity was correlated with reduced cystic growth of cystic cells in three-dimensional cyst assays. Taken together, our results suggest that JAK2 is a key signalling molecule that functions to inhibit cystic growth in cystic tubular epithelial cells, thus providing the foundation for its development as a novel therapeutic in polycystic kidney disease.

Multilocular Cystic Renal Cell Carcinoma: Our Experience

Multilocular cystic renal cell carcinoma is now recognized as an independent pattern by WHO; it is a rare malignancy with a predominantly cystic growth, characterized by very low oncologic evolution and then susceptible to conservative treatment. In the kidney cystic masses of different origin may arise, i.e. due to malformation, acquired disease or tumor. Renal neoplastic lesions may have a cystic or pseudocystic component. There are also four types of neoplasm with a predominantly cystic growth, including the multilocular cystic carcinoma, which are macroscopically very similar and impossible to differentiate through diagnostic pre-operative images. The Authors present four cases of multilocular cystic renal cell carcinoma diagnosed in the 2000–2007 period, with special reference to diagnostic difficulties and to pre- and intra-operative features of the neoplasm. In conclusion, the extemporaneous histological preoperative diagnosis of multilocular cystic renal cell carcinoma is not possible because it requires extensive sampling; furthermore, the final histological diagnosis sometimes needs particular immunohistochemical procedures to be confirmed.