Polycystic Kidney Disease: Traditional Chinese medicine inspires modern-day therapy

Kavita Mistry
By Kavita Mistry November 29, 2008 15:18

 

It’s hard to ignore the growing craze surrounding the use of traditional Chinese medicines as alternative therapies.

With millions of prescriptions dispensed every year, it seems as though Western consumers— frustrated with high prices, low efficacy, and the battery of side effects that come with commercial drugs—have turned to the 3000-year-old natural remedies for every ailment from acne to impotence.

While big pharmaceutical companies see little financial advantage in pursuing complicated cocktails of herbs with myriad active ingredients and intricate modes of action remain yet to be elucidated, it comes as no surprise that university researchers have taken significant interest in traditional Chinese medicines as possible sources of small-molecule drug candidates.

Just last year, a team led by Professor Craig Crews of Departments of Molecular, Cellular, & Developmental Biology, Pharmacology, and Chemistry) stumbled onto an herb that could potentially be of use in treating Autosomal Dominant Polycystic Kidney Disease (ADPKD), a systemic genetic disease that manifests itself in the proliferation of large, painful, fluid-filled kidney cysts (benign tumors).

According to Crews, patients “…go from a kidney that’s twice the size of normal at diagnosis to kidneys that can be upwards of two liters, the size of a big soda [bottle].” ADPKD is not only the fourth largest cause of renal failure, but it also accounts for about 5-10% of all European and North American renal transplantations.

Cutaway view of a polycystic human kidney.

Interestingly enough, ADPKD—little known when compared with diseases such as Down’s syndrome, cystic fibrosis, sickle cell anemia, hemophilia, and muscular dystrophy—affects 600,000 patients in the United States and over 12.5 million worldwide, more than do all of the previously mentioned diseases combined.

Despite the ubiquity of the condition, the only known treatments at this point are transplantation and chronic dialysis. “For pain relief,” Crews says, “they’ll go in surgically every so often and lance the cysts. But that’s about it.” As a result of this lack of an available drug therapy, approximately half of all patients will suffer from end-stage renal disease by age 60.

From a molecular point of view, mutations in the PKD2 gene (discovered on chromosome 4 in 1993) and in the PKD1 gene (discovered on chromosome 16 in 1985) that code for the proteins polycystin-2 (a calcium transporter) and polycystin-1 (pc-2’s regulatory protein), respectively, can result in polycystic kidney disease.

Both of these proteins are crucially localized to the plasma membrane of renal tubule cells, where they sit on primary, nonmotile cilia. These cilia are crucial sensory organs, as they bend in response to flow of filtrate through the tubule.

This bending, in turn, gives the signal for pc-2 to open, allowing Ca2+ ions to flood into the cell, causing cell cycle arrest, and preventing uncontrolled cyst formation. When this elaborate pathway is disrupted by mutations in either of the two polycystins (or by other mutations resulting in either shortened or absent cilia), the disease phenotype will result.

Serendipity Steps In

The Crews lab has shown that triptolide— a small diterpene triepoxide molecule derived from the traditional Chinese medicine Lei Gong Teng, often served in teas and used as an anti-inflammatory and anti-cancer agent—can interact with pc-2. Through this non-covalent binding interaction, the drug can induce the pc-2 mediated Ca2+ ion release that ends cell growth and prevents cyst proliferation.

Further experiments conducted with Professor Stefan Somlo, discoverer of the PKD2 gene and section chief of nephrology at Yale School of Medicine, showed that introducing triptolide into a mouse model of polycystic kidney disease actually corrects faulty calcium signaling, thus preventing cyst formation and disease progression. How did these discoveries actually come about?

According to Crews, “This was all actually the result of an accident.” Dr. Stephanie J. Leuenroth, a member of Crews’ Lab decided to try a different growth medium for her cells one day. Sure enough, this calcium-deficient media gave some results that had not been seen before.

“We focused on the binding activity of triptolide and triptolide-like molecules in cells,” says Crews. Leuenroth continues, “In the absence of calcium, triptolide bound at higher levels than in the presence of calcium containing media.”

Thus, the lab was able to narrow their search for a putative triptolide-binding protein to plasma membrane calcium channels. They quickly were able to identify pc-2 as the target of triptolide.

Leuenroth sums up, “Once we had the results from the protein purification and MALDI-MS identification of the polycystin- 2 calcium channel, that result made a lot of sense…The calcium experiment was a lucky break.”

A comparison between a normal mouse kidney (red) and one with ADPKD (beige).

Triptolide: A New Drug Candidate?

Although the mode of action is still largely unknown, triptolide presents an interesting pathway for further exploration. Crews warns that based on what is known about triptolide binding, the drug cannot reverse cyst formation once it has already occurred, as it only works to induce cell cycle arrest at the proper time and to stop cyst formation from occurring in the first place.

Nevertheless, he argues that it presents an attractive drug candidate for pharmaceutical companies. “Clearly, these mixtures have some type of effect or they wouldn’t have been used for literally millennia,” he says of traditional Chinese medicines. “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.”

Leuenroth adds, “In the beginning, we had no idea where this research would take us. Now, I guess the ultimate ‘dream’ would be that triptolide could be developed as a therapeutic agent to treat ADPKD but also I think it opens the door to begin looking at other possible small molecules that could also have an effect on polycystin-2 channel activity.”

So, does this mean that we should all be taking a cup of Lei Gong Teng tea three times a day? According to Crews, “That probably wouldn’t be the best idea. In fact, one of the other Chinese names for the Lei Gong Teng ‘Thunder God Vine’ is something roughly to the effect of ‘Take ten steps and die’.”

Of course, this shouldn’t be surprising, as the Lei Gong Teng tea—just like most other traditional Chinese medicines—contains not only triptolide, but a vast array of other potent chemicals that could have potentially harmful effects on the body. There’s clearly a long way to go for ADPKD patients, but for now, it’s a wonderful start.

Professor Craig Crews with some packages of Le Gong Teng tea.

About the Author
KAVITA MISTRY is a sophomore in Berkeley College.

Acknowledgements
Thanks to Professor Craig Crews and Dr. Stephanie Leuenroth for their thoughtful words.

Further Reading
Crews, Craig M. Triptolide is a traditional Chinese medicine-derived inhibitor of polycystic kidney disease. PNAS. 104(11): pp 4389–4394.

Kavita Mistry
By Kavita Mistry November 29, 2008 15:18