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KU Medical Center scientists identify mechanism for critical function of a damaged protein that causes most polycystic kidney disease

Their work will inform the design of drugs aiming to one day restore the function of that protein in order to prevent or treat the disease.

Colorful illustration of polycystic kidney disease (PKD) showing cysts formed on kidneys.
Polycystic kidney disease causes fluid-filled cysts to form in the kidneys. More than half of patients will develop kidney failure by age 60 and need dialysis or kidney transplantation.

To fix any piece of machinery — an airplane engine, a lawn mower, a computer motherboard —you first have to understand the function of each of its parts and how those parts work together. That’s also true for the biological machinery that performs countless tiny tasks in the human cell to make the organs and tissues in our bodies work properly.

In her laboratory at the University of Kansas Medical Center, Robin Maser, Ph.D., associate professor of clinical laboratory sciences at KU School of Health Professions, is trying to understand the function of a cellular protein known as polycystin-1 that, when damaged, is responsible for an inherited form of polycystic kidney disease (PKD) that accounts for 85% of PKD cases. 

The fourth leading cause of kidney failure, PKD causes fluid-filled cysts to form in the kidneys and impair their function. It can also cause cysts in the liver, pain in the back and abdomen, high blood pressure and cardiovascular problems.

The mutant polycystin-1 protein implicated in PKD is produced by a damaged PKD1 gene. “The million-dollar question is, if the gene was not damaged and thus the protein were functioning correctly, what exactly would that protein do and how would it do that?” said Maser.

In her latest study, published in Proceedings of the National Academy of Sciences, Maser and her colleagues have solved part of that puzzle. She and her colleagues have discovered the mechanism by which polycystin-1 initiates cell signaling, a critical form of communication from the outside to the inside of cells.

Specifically, the part of the polycystin-1 protein that extends outside the cell splits in two, shedding one part and thus exposing a small part of the protein (called the stalk or stachel, meaning “stinger” in German) that remains within the cell membrane. The stalk then attaches to the remaining part of the protein, which then triggers activation of cell signaling.

But if polycystin-1 is mutated, and cell signaling doesn’t happen, the cell cannot adapt to its outside environment and disease can occur.

The study “provides some really elegant biochemistry and structural biology to show in detail how the protein does all of this,” said Alan Yu, M.B., B.Chir., director of the Jared Grantham Kidney Institute at KU Medical Center. “But the details aren’t as important as the fact that Dr. Maser has now figured out what is likely the central role of this protein, and by inference what is responsible for causing PKD when it is mutated.”

The work Maser conducted in the lab using a kidney cell line was duplicated by Yinglong Miao, Ph.D., associate professor at the Center for Computational Biology and Department of Molecular Biosciences at the University of Kansas and an author on the study. Miao created computer simulations of polycystin-1, the results of which matched Maser’s lab results.

This work builds on research that KU Medical Center has been conducting for decades. The Jared Grantham Kidney Institute is named for the renowned physician who conducted seminal research in PKD. Maser, whose own father died of PKD, was, ironically, working on a different line of research in the mid-1990s when James Calvet, Ph.D., deputy director of the Kidney Institute, was her postdoctoral advisor and began collaborating with Grantham. “I knew nothing about the disease,” remembered Maser. “And my father had died way before then. It goes to show how little knowledge there is.”

There is currently just one FDA-approved drug for PKD, tolvaptan, but it’s approved only for adults, is not a cure and has some uncomfortable side effects, including thirst and frequent urination.

Now that the researchers understand this part of the disease process, that knowledge can be used as the basis of drug design. “If we understand [how the protein is supposed to function], then we can design therapies that, instead of addressing symptoms, actually try to fix the function of the protein,” said Maser. “What we're hoping is to be able to make a drug we can give people with PKD that will be able to restore signaling of polycystin-1 to a sufficient level to either dampen the disease or prevent it.”

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