Advances in polycystic kidney disease research
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disorder with a prevalence of more than 1:1 000. Patients develop renal cysts, and slowly progress towards end-stage renal disease. Current therapy is directed towards limiting the morbidity and mortality from these complications, while effective targeted treatments are lacking. Therefore, innovative approaches are necessary to unravel disease mechanisms and develop novel interventions. The EU-funded TRANCYST project designed a multidisciplinary programme for training young scientists in ADPKD research and treatment development. Different animal (mouse, zebrafish) and cell models were generated to investigate disease mechanisms. Results unveiled critical molecular processes involved in establishing and maintaining renal polarity and cellular integrity. Profiling and drug screening experiments identified potential therapeutic targets. In addition, scientists discovered that ADPKD is associated with specific defects in the transport of various solutes in the kidney. This occurs early in the progression of the disease and before the development of massive cysts. Transport impairment seems to be associated with alterations of the primary cilium, a structure present at the cell surface that senses extracellular stimuli. Special focus was given to two signalling pathways, namely planar cell polarity (PCP) and Hippo pathway, as these were deregulated in ADPKD. Additionally, the hepatocyte nuclear factor 1 beta (HNF1b) protein regulated expression of several ADPKD genes and was impaired in patients through naturally occurring mutations. Gene expression analysis of the mouse model of the disease identified a robust PKD expression signature mainly linked to injury repair processes. Specific gene clusters that correlated with cyst formation and disease progression responded to specific treatments, constituting important therapeutic targets. Furthermore, several compounds were identified as drug leads for the treatment of ADPKD. Finally, scientists discovered biomarkers in patient samples and developed a urinary prognostic test that accurately predicts relevant clinical endpoints in ADPKD. Taken together, the deliverables of the TRANCYST study are expected to improve early diagnosis, accurate monitoring and treatment of ADPKD.
Keywords
Polycystic kidney disease, biomarker, TRANCYST, injury/repair, HNF1b
