Disease Finding May Lead to a New Treatment
||Molecular biologist Thomas
Weimbs directs the lab that discovered how a certain type of
polycystic kidney disease originates.
at UC Santa Barbara have discovered a cellular malfunction that
suggests possibilities for drug therapy for a certain type of kidney
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
“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
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.