Importance of Cilia in Inherited Kidney Disease a Focus of Yale Researchers

Identification of a genetic alteration of the cilium on kidney tubule cells leads to the cause of a common and devastating kidney disease, according to Yale researchers presenting their work at a recent meeting of the American Society of Nephrologists in San Diego, in a symposium entitled “Cilia: A Neglected Organelle” and in other reports.

Cilia in many different cell types are motile filaments, whose movement propels fluids over cell surfaces; kidney cilia do not move on their own. Most textbooks describe kidney cilia as having “no function,” being “vestigial,” or “of unknown function.” This is no longer the idea.

Meeting reports showed that one of the most prevalent and destructive human kidney diseases, autosomal dominant ploycystic kidney disease (PKD) is keyed to these cilia. PKD, a genetic disorder that strikes as many as 1 in 500 people, is characterized by the formation of large cysts caused by uncontrolled kidney epithelial cell division.

Papers were presented by professors Joel Rosenbaum (Molecular, Cellular & Developmental Biology), Michael Caplan (Physiology and Cell Biology) and Sterfan Somlo (Internal Medicine, Nephrology and Genetics) at Yale and their colleagues George Witman and Greg Pazour at the University of Massachusetts Medical Center, and Maureen Barr from the University of Wisconsin.

Rosenbaum’s group studies the assembly of the flagella of a small green alga, Chlamydomonas. Cilia and flagella are similar. They showed that a motility process termed intraflagellar transport (IFT) was required for the assembly and maintenance of the flagella, and that the genes coding for the IFT process were present in all cells that had cilia or flagella. When the genes were mutated, the flagella did not form.

They were surprised to find that one of the genes they had cloned from the alga, was previously identified in the mouse and, when mutated, gave rise to Polycystic Kidney Disease (PKD). Observations by electron microscopy of the kidneys in mice with PKD pathology, showed that they, like the mutated alga, lacked normal cilia.

The link between PKD and the kidney cilia was tightened when it was demonstrated that ion channels, called polycystins, known to be defective in PKD, were localized to the kidney cilia. Therefore PKD can arise, either from defects in the polycystin ion channels or from an inability to form normal cilia, upon which these channels normally reside.

Studies on the sensory cilia of the worm, C. elegans also defined this relationship between the cilia and PKD. Researchers demonstrated that polycystin channels resided on the cilia, and that the worm’s ability to sense its surroundings could be affected either by mutations in the channels themselves, or by mutations in the IFT process and the worm’s ability to form cilia.

Why are cilia so important for kidney function?

Workers at the National Institutes of Health and at Yale showed that mechanical movement of the kidney cilia causes a massive influx of calcium into the kidney cells, and that the calcium almost certainly travels through the polycystin ion channels on the cilia. These findings suggest the kidney cilia probably act as mechanical sensors that respond to fluid flow in the kidney by bending, and admitting calcium through the polycystin channels on their surface in the process.

Caplan and Somlo from Yale reported, at these meetings, that that when kidney cilia are mechanically bent, and calcium flows into the cells, a piece of the calcium channel is clipped and goes to the nucleus where it affects transcriptional regulation from genes. This provides a direct link between the mechano-sensory calcium channels on the ciliary membrane and nuclear regulation of the cell. The research is some of the first evidence linking the function of polycystin ion channels on the ciliary membrane to the transcription of messenger RNA from the nuclear genome.

Most of the work on PKD is supported by grants from the NIH, and Rosenbaum’s Lab has recently received an NIH MERIT award grant totaling $4.5 million for studies on the role of cilia in disease.