Cyst formation in the PKD2 (1-703) transgenic rat precedes deregulation of proliferation-related pathways

In this study we focused on the cystic phenotype since birth in an attempt to clarify the temporal contribution of cellular proliferation in cyst development. Using a PKD2 transgenic rat model (PKD2 (1-703)) of different ages (0-60 days after birth) we performed gene expression profiling and phenotype analysis by measuring various kidney parameters.Phenotype analysis demonstrated that renal cysts appear immediately after birth in the PKD2 transgenic rat model (PKD2 (1-703)). On the other hand, abnormal proliferation occurs at later stages of the disease as identified by gene expression profiling. Interestingly, other pathways appear to be deregulated at early stages of the disease in this PKD model. Specifically, gene expression analysis demonstrated that at day 0 the RAS system is involved. This is altered at day 6, when Wnt signaling and focal adhesion pathways are affected. However, at and after 24 days, proliferation, apoptosis, altered ECM signaling and many other factors become involved.Our data suggest that cystogenesis precedes deregulation of proliferation-related pathways, suggesting that proliferation abnormalities may contribute in cyst growth rather than cyst formation.Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common inherited monogenic disorders in humans, with a prevalence of about 1:1000. It is characterized by the formation of bilateral fluid-filled cysts that increase in size and destroy the renal parenchyma, leading to end-stage renal disease (ESRD). ADPKD can be caused by mutations in either the PKD1 (~85% of cases) or the PKD2 gene (~15% of cases), which encode for polycystin-1 (PC-1) and polycystin-2 (PC-2), respectively.Although all cells in ADPKD patients carry the same germline mutation, cysts form in only a minority of nephrons. The disease is thought to act as recessive on the cellular level, as it has been shown that the somatic gain of a 'second hit' in the allele inherited by the healthy parent is necessary