AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD): MOLECULAR AND CELLULAR MECHANISM OF PATHOGENESIS AND IMPLICATIONS FOR TREATMENT OF THE DISEASE

One of the most common inherited disorders in humans, Autosomal Dominant Polycystic Kidney Disease (ADPKD), affects approximately one person in a thousand worldwide. This slowly progressive disease causes normally hair-thin tubules in the kidney to balloon into thousands of fluid-filled structures called cysts. The cysts increase in size and number throughout an individual's lifetime and approximately half of all patients progress to renal failure, requiring dialysis or transplant. There are no therapies to date for this disease. Mutations of a gene called PKD1 cause about 85% of all ADPKD cases. The normal product of this gene is a huge protein located on the surface of tubule cells. The protein's structure suggests that it recognizes specific molecules within the scaffolding that supports the cells (the extracellular matrix) and transmits this information into the cell's interior. In ADPKD patients, the PKD1 protein is defective and cannot transmit information. This failure causes kidney tubule cells to form cysts. I have now developed a simple new system to study this process. I used commonly studied tubule cells, called MDCK cells. These cells were originally isolated from kidneys and have been adapted to grow in laboratory cultures. These special cells lack PKD1 and therefore produce cysts. When I injected a "minigene" that codes for the normal PKD1 protein these cells produce the PKD1 protein and form tubules rather then cysts. This model is easy to manipulate and can now be used to understand how normal polycystin induces tubules. I can now study which molecules in the extracellular scaffold interact with the PKD1 protein and how this is transformed into a signal capable to instruct the cells to work properly and form tubules. Understanding this basic process is right now our strongest hope that one day we could "fix" the PKD1 protein disrupted in ADPKD patients.