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Clues about kidney disease from an unexpected direction

Karlene Cimprich, PhD, is a Stanford professor who normally studies how cells keep their strands of DNA in proper working order. Her newly published research (subscription required) provides insights into the DNA repair process, but as a very interesting bonus it also turns up a new avenue for drugs to treat kidney disease. The unifying factor for these disparate discoveries is the mysterious antenna-like cellular structure called the primary cilium.

Most people don't realize that nearly every cell in the human body has an antenna. Well it does, even though the rod-like projection was overlooked for decades after its discovery more than 100 years ago. An article I wrote in Stanford Medicine magazine explains:

The primary cilium is not a recent discovery. Swiss anatomist K.W. Zimmermann described the structure and suggested a sensory role in 1898, but other scientists largely ignored it. In later years it was written off as a quirk of evolution. The outburst of research over the past decade has revealed that the tiny projection is acting as the receiving station for cells' signaling chains, the communication networks that govern and coordinate cell actions.

In the past two decades scientists have started paying attention to the primary cilium, and they've discovered not only its receiving-station role, but its importance for health.

Cimprich's research started out having nothing to do with the primary cilium. About five years ago, Renee Paulsen, then a graduate student in her lab, launched a search for proteins needed to repair damage to a cell's DNA. Another graduate student, Claudia Choi, assessed some of those proteins that were especially needed to repair DNA when the cells were stressed.

One of the big hits was a protein called NEK8.

A literature search revealed intriguing info about NEK8: It's also faulty in certain kidney diseases — which are known to result in part from defective primary cilia.

This led Cimprich and her team to the work reported today in Molecular Cell: details of the molecular mechanism NEK8 uses to prevent DNA damage and clues to how NEK8’s malfunction relates to the primary cilium and kidney disease.

One of their experiments (conducted in tiny roughly spherical balls of cells modeling kidney tissue), carried out with their collaborators Rachel Giles, PhD, and Gisela Slaats, PhD, at University Medical Center Utrecht in the Netherlands, showed that a defect in primary cilia formation resulting from a lack of functional NEK8 could be rescued by adding a chemical that inhibits an enzyme called CDK or cyclin-dependent kinase. Cimprich's lab showed that this enzyme was ramped up in cells lacking NEK8 and was responsible for the DNA damage occurring.

These observations are really interesting because many drug companies are testing CDK inhibitors as cancer treatments (subscription required). Could it be that these same compounds could reverse some forms of kidney disease?

This would be great news, Giles explained: "Renal ciliopathies [abnormalities of cilia in kidney cells] are after all the main cause of renal failure in children and young adults, and it is likely that chronic kidney disease, one of the largest problems associated with cardiovascular disease in adults, works by similar if not identical processes. The only treatment currently available is kidney transplantation or dialysis."

Meanwhile, while it's increasingly clear that the primary cilium is playing an important role in the DNA damage response, what that role is remains mysterious.

"Nobody has any idea what the basis is yet. This is the big black box," says Cimprich.

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