Brewing a new treatment for kidney disease

Swirled in a cup, tea leaves are said to offer a glimpse into the future. Now, Yale researchers have shown that one kind of Chinese tea may change the future for patients with polycystic kidney disease (PKD), an inherited genetic disorder in which the formation of multiple renal cysts leads to kidney failure. The disease is the most common life-threatening genetic disorder worldwide, affecting some 12 million people. There is no cure, and the only effective treatments for PKD-induced renal failure are dialysis and kidney transplants.

A team led by biochemist Craig M. Crews, Ph.D., recently showed that triptolide, a compound found in the thunder god vine, a medicinal plant used to make the traditional Chinese tea known as lei gong teng, activates a cascade of molecular events that stops kidney cysts from forming.

“Triptolide has been looked at, and is still being looked at, as an anti-tumor agent,” explains Crews, associate professor of molecular, cellular and developmental biology, chemistry and pharmacology. “Yet they don’t know how it works. Our thinking all along is that we’d love to know how it works so that we can anticipate potential side effects as well as come up with different compounds that work in the same way.”

To find out, Crews made a radioactive version of triptolide, added it to kidney cells and tracked where it went. He found that the compound clustered around a protein called polycystin-2, a calcium channel found in kidney cells that is mutated in many cases of PKD.

During normal development, kidney cells arrange themselves into tubules that course through the organ. When the cells finish this assembly, urine flows through the tubules and bends a protein called polycystin-1, which is found on tiny hair-like extensions of the cells. Polycystin-1 then signals a partner protein, polycystin-2, to release calcium from internal stores, which stops the tubule growth. In people with inherited mutations in either polycystin gene, this message to stop tubule formation is silenced.

“When these cells can’t sense or can’t respond to urine flow, they think they are at an earlier stage in development,” says Crews. “And they say ‘Well, you know what? We need to make a tubule’ and they keep growing and they form a cyst.” People with inherited polycystin mutations usually start noticing symptoms of kidney disease around age 25, Crews says. “Then they go from a kidney that’s twice the size of normal at diagnosis to kidneys that can be upwards of 2 liters, the size of a big soda pop.”

Working with Postdoctoral Associate Stephanie Leuenroth, Ph.D., and Stefan Somlo, M.D., the C.N.H. Long Professor of Medicine and chief of nephrology, and colleagues, Crews went on to show that triptolide, when it binds to polycystin-2, stops kidney cysts from growing: in mice engineered to have polycystin-2 mutations, triptolide reduced the size of kidney cysts by 50 percent. Somlo, one of the world’s leading experts on PKD, was the first scientist to identify polycystin-2.

Triptolide is now in early clinical trials as a cancer treatment, and the researchers hope their PKD findings will help accelerate clinical tests of triptolide in kidney disease.

Crews says the new findings strengthen his opinion that traditional Chinese remedies hold vast untapped potential for new medicines.

“Clearly, these mixtures have some type of effect or they wouldn’t have been used for literally millennia,” he says. “The challenge for Western researchers is to try to identify what the active ingredient is. Then, as I did with triptolide, we can find out how it works.”