U.S. Department of Health and Human Services

Regulation of Cyst Growth in Polycystic Kidney Disease:

Scientists have discovered a link between two proteins known to contribute to the most common form of polycystic kidney disease (PKD) and a cell-surface structure in a subset of kidney cells in mice.

PKD is a genetic disorder characterized by the growth of numerous luid-illed cysts in the kidneys. For many people who have the more common form of the disease, autosomal dominant PKD (ADPKD), these cysts grow slowly over many years. Over time, they can profoundly enlarge the kidney and replace much of the organ’s normal structure. This results in reduced kidney function that can potentially lead to kidney failure.

It is thought that cyst growth arises from improper growth signals in the kidney. Previous studies have shown that the removal of cilia, tiny, hair-like structures on the surface of some kidney cells, could produce cysts. Mutations in the proteins polycystin-1 and polycystin-2 have also been found to cause kidney cysts and cause ADPKD.

It is thought that cilia act to sense luid low in the kidney. The polycystins are present in the cilia, where they form a complex that has been hypothesized to aid in this low sensing. To explore this relationship, researchers used a series of genetically engineered mice in which they could selectively delete polycystin-1, polycystin-2, and/or the cilia in the kidney. When they deleted polycystin-1 and/or -2, the mice developed kidney cysts. When the scientists next deleted the cilia in these mice, they found that cyst growth slowed dramatically. Interestingly, the severity of the cysts was related to the time interval between the loss of polycystin function and the loss of cilia: the longer the interval, the worse the cysts became before their growth slowed. This suggests that, under normal conditions, the polycystins may act as a brake on cyst-promoting signals arising from cilia. Loss of polycystin functions allows the cilia signal to proceed unabated, while deletion of cilia removes this stimulation.

These indings in mice have important implications for researchers’understanding of the molecular basis of kidney cysts. In people with ADPKD, most cysts are slow-growing, and people can live with the disease for decades before they develop symptoms. If similar mechanisms lead to kidney cyst development in people with ADPKD, then the design of strategies to inhibit the function of cilia that are associated with polycystins in these individuals before extensive kidney damage occurs could have profound implications for patient care.

Ma M, Tian X, Igarashi P, Pazour GJ, and Somlo S. Loss of cilia
suppresses cyst growth in genetic models of autosomal dominant
polycystic kidney disease. Nat Genet 45: 1004-1012, 2013.