image: University of Oklahoma College of Medicine researchers Maulin Patel, Ph.D., left, and Leonidas Tsiokas, Ph.D., are seeking the mechanisms of polycystic kidney disease.
Credit: University of Oklahoma
OKLAHOMA CITY – Polycystic kidney disease (PKD), a family of genetic disorders that causes clusters of cysts to form on the kidney, is among the most common genetic disorders, affecting some 500,000 people in the United States. Roughly one in every 1,000 people will develop some form of cystic kidney disease during their lifetime, and nearly 40,000 Oklahomans have a chronic kidney disease, according to the Oklahoma Health Care Authority.
For many patients, dialysis – a time-consuming and costly procedure – is one of few treatment options. A 2021 study by researchers at Tufts University found that the average annual cost of dialysis for patients in the United States is about $40,000.
Now, new research from the University of Oklahoma aims to unravel the genetic mysteries of this disease and, in the process, open the door to novel therapies.
Researchers have long understood that PKD is associated with kidney cysts and fibrosis and a gradual decline in renal function – a measure of the kidney’s ability to remove waste and fluid from the body. A key unresolved question is what drives the renal function drop-off.
“When people have mutations in certain genes, they can end up with kidney cysts, which alter the tubular architecture of the organ,” said Leonidas Tsiokas, Ph.D., a professor of cell biology at the OU College of Medicine and lead investigator for the study. “What we don’t know is exactly how you go from a normal kidney to a cystic one.”
Since late 2024, Tsiokas and colleagues at OU Health Sciences have begun research funded through a four-year, $2 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. A key focus of the study is to identify genes and associated proteins responsible for PKD and their contribution to renal function.
“We know of about 40 genes that play a role in polycystic kidney disease. But these genes have yet to explain the trigger of how you can go from a normal tubule to an elongated tubule to a tubule where the diameter is affected and not functioning,” he said.
“In other words, we know the result of mutated genes, but we don’t know the cellular process by which this disease develops.”
To address these questions, Tsiokas and Maulin Patel, Ph.D., a postdoctoral research fellow in Tsiokas' lab, are zeroing in on Fbxw7, a gene known to play an important role in basic cellular functions that could be linked to cystogenesis, fibrosis, and cellular death and degeneration. Its role in PKD had never been examined before.
Tsiokas speculated that by genetically deleting Fbxw7 in a mouse model used to study kidney function, he could re-create the process of cystogenesis in mice. Preliminary data suggest he’s correct.
“When Fbxw7 is deleted, we found that (those) mice develop slowly progressing cystic kidney disease without kidney enlargement, tubulointerstitial fibrosis, tubular degeneration, and a progressive decline in kidney function,” Tsiokas said. Importantly, the changes observed are cardinal features of several types of PKD, including nephronophthisis (NPHP), a genetic kidney disorder that affects children. One in 50,000 children worldwide suffers from nephronophthisis.
Further study of the mice with the Fbxw7 gene deletion revealed that renal function declines were connected to an abnormal accumulation of a protein called SOX9. Normalizing its levels by genetically deleting just one copy of the SOX9 gene restored overall renal function, Tsiokas said.
Tsiokas said these findings offer the first conclusive evidence of the genes that directly modulate fibrocystic diseases of the kidney and are an essential step in efforts to identify “druggable targets” for genetic forms of cystic kidney disorders. Future work will seek to catalog how cystogenesis develops, how it is modulated by fibrosis or tubular degeneration, and how these processes interact to impact renal function.
“Understanding these processes will give us fresh ideas of how to delve further into the mechanisms of the pathogenesis of cystic kidney disease and how we might treat it,” he said.
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About the Project
The research is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, award No. R01DK138339.