November 15, 2019
Keio University School of Medicine
A joint research group including Researcher Kentaro Fujii and Professor Hiroshi Ito of the Department of Internal Medicine (Nephrology, Endocrinology, and Metabolism), Project Associate Professor Kazuki Miyashita of the Endowed Department of Chrono-Endocrinology, and Assistant Professor Akiko Kubo of the Department of Biochemistry, all at the Keio University School of Medicine, has revealed through experiments using mice that febuxostat, a urate-lowering drug, suppresses the progression of renal damage by promoting ATP resynthesis in renal tubular cells.
It is known that as renal damage worsens, it can ultimately lead to a serious condition (end-stage renal failure) requiring lifelong dialysis or kidney transplantation. In recent years, attention has been drawn to the fact that repeated episodes of acute renal failure due to transient decreases in renal blood flow can transition to chronic kidney disease, but the detailed mechanism of renal failure progression remains unclear.
In this study, to investigate how quantitative changes in metabolites due to decreased blood flow (hereafter, insufficient blood flow) are involved in the progression of renal damage, we used mass spectrometry imaging, a new research method that visualizes metabolites within organs, to observe the kidneys of mice whose renal blood flow was blocked by renal artery clipping.
The results showed that a 10-minute blockage of blood flow caused an 80% decrease in ATP in the renal cortex, which is the cell's energy source, leading to a decline in kidney function. We also found that even 24 hours after blood flow was restored, ATP levels remained 20% lower and did not return to their original levels.
Therefore, we examined the effect of febuxostat, a drug that suppresses the breakdown of ATP into uric acid, on ATP levels in various parts of the kidney. When febuxostat was continuously administered to mice after a 10-minute blood flow blockage followed by reperfusion, we found that the drug promoted ATP recovery via adenylate resynthesis and suppressed renal damage.
This discovery indicates that the decline in renal function associated with insufficient blood flow can potentially be improved by controlling cellular metabolism. This is a significant finding that could lead to the development of new therapeutic strategies for renal failure, a serious condition with few effective treatments that ultimately requires dialysis.
The results of this research were published in "JCI Insight" on November 14 (US Eastern Time).
Please see below for the full press release.