Successful recovery of advanced renal fibrosis announced

There are approximately 20 million patients in Japan with chronic kidney disease (CKD). Once fibrosis, in which the kidneys become hardened, progresses, there is no treatment available, and it is almost impossible to recover reduced renal function. A research group, including Professor Hirokazu Okada, Graduate Student Wakako Kosakai, Associate Professor Tetsuya Sato, and Professor Tsutomu Inoue at the Faculty of Medicine at Saitama Medical University, using a mouse CKD model, discovered for the first time in the world that compound 3k, a pyruvate kinase M2 (PKM2) inhibitor, can restore advanced kidney fibrosis.

This is an important discovery that represents a strategy for the development of new therapeutic agents for chronic kidney disease, which was thought to be irreversible. If treatment via oral medication becomes possible, it is expected to help patients maintain and improve their quality of life by avoiding dialysis, while also reducing dialysis-related medical costs, which are estimated at 1.5 trillion yen annually. The study was published online in the Journal of Biological Chemistry.

As CKD progresses and triggers renal fibrosis, healthy tissue is replaced by hard fibers like collagen, causing the kidneys to stiffen and shrink. Fibrosis is caused by stress on the kidneys from a variety of causes, including diabetes, hypertension, and nephritis. In a damaged kidney, low oxygen and ischemia progress, causing changes in how cells produce energy. It has become clear that this metabolic shift promotes fibrosis.

The research group focused on PKM2, which plays a key role in metabolic abnormalities. While PKM2 normally handles metabolism in the cytoplasm of a cell, it moves into the nucleus when the kidney is injured. There, it acts as a transcriptional co-factor that switches on genes that cause fibrosis. The team believed that inhibiting PKM2 could stop this process.

First, they examined the effects of the PKM2 inhibitor compound 3k using a mouse model of chronic kidney disease (the UIRI model). In the UIRI model, progressive kidney shrinkage and fibrosis are typically observed, but the administration of compound 3k significantly suppressed these effects. It is noteworthy that efficacy was confirmed not only in the early treatment group, in which treatment was started 1 day after injury, but also in the delayed treatment group, in which treatment was started 7 days after injury.

In fibrotic kidneys, gene expression levels of fibrosis-promoting proteins such as CCN2 are elevated, and 3k administration was found to suppress this phenomenon. Fluorescent immuno-staining was to observe the localization and expression of YAP1, a factor that promotes cell growth and fibrosis genes. The research group saw strong staining in advanced fibrotic tissue and noticeable localization of cells forming tubular structures in the cytoplasm and the nucleus.

Additionally, LTL staining (a marker for proximal tubules) confirmed the presence of tubule damage and shrinkage. Both the early and delayed treatment groups did not show these changes, indicating that compound 3k suppresses gene expression that promotes fibrosis. Furthermore, in a fibrosis model system using human kidney-derived HK-2 cells, the induction of expression of CCN2, a fibrosis-promoting factor, was also suppressed by compound 3k.

Through Western blot analysis of cell fractions, they revealed that compound 3k inhibits PKM2, YAP1, and beta-catenin from moving into the nucleus. Co-immunoprecipitation experiments also proved that in HK-2 cells where fibrosis was induced, PKM2 forms a complex with YAP1 and beta-catenin.

These results clarify that PKM2 acts as a transcriptional co-factor that switches on fibrosis-causing genes. Compound 3k has the inhibitory activity to stop PKM2 from entering the nucleus. Since this action was effective in recovering from damage even when administered after the kidney injury had progressed, it is a vital starting point for developing new drugs for human chronic kidney disease.

Moving forward, the research group will work on improving the compound's solubility, bioavailability, and specificity to develop it into an oral medication. They aim for early practical application by verifying its effectiveness through clinical research.

Journal Information
Publication: Journal of Biological Chemistry
Title: PKM2 inhibitor suppresses kidney fibrogenesis by disrupting YAP-TEAD-CCN2 transcriptional signaling following ischemia-reperfusion injury
DOI: 10.1016/j.jbc.2025.111029