for lethal kidney disease
A treatment for polycystic kidney disease (PKD), a leading cause of fatal kidney failure worldwide, has been identified by a research team led by Yale biochemist Craig Crews, according to a report in the Proceedings of the National Academy of Sciences.
Over 12 million people worldwide suffer from PKD, a genetic disorder that causes uncontrolled growth of cells lining tubules in the kidneys, resulting in the formation of many large fluid-filled cysts in the kidneys.
"Unfortunately, aside from kidney transplantation, there has been no cure for PKD, nor has there been a suitable drug treatment to slow its progression," says Crews, associate professor of chemistry, and of molecular, cellular and developmental biology, and of pharmacology. People with PKD have a shortened life expectancy and require life-long treatment. "We hope that is about to change," he adds.
Crews has been studying a variety of traditional Chinese medicines (TCMs) in order to understand the biology and chemistry of how they work. Lack of knowledge of these processes, he says, has been a roadblock in the adaptation of TCMs for medical treatments in the West.
Crews and colleagues showed that a substance called triptolide causes cell growth arrest in certain cell types. Triptolide is a potent, biologically active compound isolated from the medicinal "Thunder God Vine," Tripterygium wilfordii Hook F. The plant is in the TCM tea Lei Gong Teng, which has been used for centuries as a therapeutic against cancer, inflammation and auto-immune diseases.
Normal kidney tubule cells have a built-in switch for regulating their growth. Two proteins, PKD1 and PKD2, are located on a bristle-like cilium that bends in response to fluid flow across the cell. During kidney development, cells destined to line a kidney tubule grow and divide until the tubule is formed, as sensed by fluid flow in the tubule. Fluid flow bends the primary cilium, giving a signal to stop cell growth. PKD is caused by a mutation in the PKD1 or PKD2 gene causing the cells to miss the "stop growing" signal, allowing them to keep growing, and thus generating a cyst.
In collaboration with Dr. Stefan Somlo, chief of nephrology at the Yale School of Medicine, who discovered the PKD2 gene, Crews and colleagues tested triptolide in a mouse model of PKD. Both fewer and smaller kidney cysts formed in mice lacking PKD1 when they were treated with therapeutic amounts of triptolide.
"Our research shows that triptolide, an active ingredient of the TCM Lei Gong Teng, markedly decreases cyst formation in a mouse model of this most common genetic lethal kidney disease," Crews says. "Our results offer a novel therapeutic approach to this deadly disease and highlight the potential of TCM as pharmaceutical sources."
Other authors on the paper were Stephanie J. Leuenroth, Dayne Okuhara, Joseph D. Shotwell and Zhiheng Yu at Yale and Glen S. Markowitz at Columbia University. The research was funded by National Institutes of Health and by a postdoctoral fellowship from the American Cancer Society.
-- By Janet Rettig Emanuel
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