Gene discovery offers hope for new kidney disease treatments

Monday, 15 April, 2024

Gene discovery offers hope for new kidney disease treatments

Researchers at Duke-NUS Medical School have identified a gene that plays a crucial role in regulating energy supply to cells that drive kidney failure. Their discovery, described in the Journal of the American Society of Nephrology, highlights a novel approach for developing treatments and drugs to halt the progression of chronic kidney disease (CKD).

CKD is a global health concern contributing to high mortality rates worldwide. In the advanced stage of kidney disease, kidney tissue becomes fibrotic, resulting in permanent scarring and irreversible organ damage. This condition often culminates in end-stage kidney failure, for which current treatment options are severely limited.

“Our research focused on myofibroblasts, a type of kidney cell central to the scarring of renal tissue in fibrosis,” said Associate Professor Jacques Behmoaras, co-senior author of the new study. “By investigating the link between the metabolic activities of these cells and the progression of the disease, we discovered that by regulating energy supply to myofibroblasts, we can control their function and potentially halt kidney fibrosis.”

Led by Associate Professor Enrico Petretto, the research team analysed over 130 biopsy samples from patients in China and Italy. Their findings revealed that the presence of the WWP2 gene in myofibroblasts is associated with the advancement of kidney fibrosis. The gene is crucial for regulating the mitochondria, also called the powerhouses of the cell because they produce the energy needed for cell functions.

“In our preclinical models of CKD, we discovered that a higher level of WWP2 rewires the cell’s metabolism, contributing to the advancement of fibrosis,” said Dr Chen Huimei, first author of the paper. “On the other hand, a lack of WWP2 boosts metabolism in renal cells and slows down scar formation, reducing the severity of kidney dysfunction and fibrosis.”

The panels in the image demonstrate how the presence of WWP2 results in more fibrotic tissue (left), while a WWP2 deficiency results in less fibrosis (right). Image credit: Duke-NUS Medical School.

In earlier studies, the team had found that WWP2 controls scarring in heart disease. Targeting the gene in patients could halt the formation of excessive scar tissue and delay progression to heart failure.

“Through our studies, we have shown that WWP2 is a new potential target for the development of drugs to halt the progression of fibrosis in several diseases,” Petretto said. “This is especially so for CKD, which can progress to renal failure and is fatal without treatment. Our findings pave the way for the design of new and promising therapies for such illnesses that would otherwise have limited treatment options.”

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, said the study “not only sheds light on the genetic mechanisms underlying kidney disease, but also opens up new avenues for therapeutic intervention, offering hope for millions of CKD patients worldwide”. The researchers are currently in talks with venture capitalists to develop inhibitors of WWP2 to treat heart and kidney disease.

Top image credit: Haneefa Nizamudeen

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