By Gail Gallessich

Scientists at UC Santa Barbara have discovered a cellular malfunction that suggests possibilities for drug therapy for a certain type of kidney disease.

An inherited kidney disease known as ADPKD, short for autosomal-dominant polycystic kidney disease, affects over 600,000 people in the U.S. In the U.S. this is more than the number of individuals affected by cystic fibrosis, muscular dystrophy, hemophilia, Down syndrome, and sickle cell anemia combined.

The disease is characterized by the proliferation of cysts that will eventually cause kidney failure in half of all patients by the time they reach age 50. Currently, no treatment exists to prevent or slow cyst formation, and most ADPKD patients require kidney transplants or life-long dialysis for survival, explained Thomas Weimbs, assistant professor of molecular, cellular, and developmental biology who directs the lab that made the discovery. It was reported in last month’s Developmental Cell journal.

Kidney cells are lined with small, hair-like cilia. The cilia sense fluid flow as urine passes through the kidney and send signals to the kidney cells that line the small canals—called tubules. It is the loss of cilia function that leads to polycystic kidneys.

“With polycystic kidneys, these tubular cells think they have to repair an injury, and they ‘repair’ it by forming lots of cysts,” said Weimbs.

The disease is triggered by polycystin-1, a large protein. If it mutates, the mutation leads to polycystic kidney disease. Even though polycystin-1 was discovered more than a decade ago, its function has remained unknown.

In this study, Weimbs and his colleagues discovered that, under normal conditions, the polycystin-1 keeps certain parts of the cell localized in the cilia and away from the nucleus. These parts of the cell are known as transcription factors. If there is an injury, the flow of urine stops and the transcription factors migrate to the nucleus of the cell. This signals the cell to divide to replace those cells that have been lost.

In patients with this disease the repair mechanism is always turned on because the polycystin-1 is defective. The discovery of this pathway opens the door to possible drug therapy for the disease.

This is because inhibition of any step along this chain of reactions could have beneficial effects. Weimbs and his team are currently capitalizing on these findings by testing drugs to specifically affect components of this novel pathway.