New Cause of Kidney Disease Exacerbation Discovered – Abnormalities in "Mechanism for Correct Protein Production" Cause Decline in Kidney Function –

(Key Points)

· Discovered that the enzyme "CDKAL1," which regulates precise protein production in the body, has a novel function in maintaining kidney health.

· When this enzyme's function weakens, the kidney's "filtering function" is impaired.

· Leads to a new understanding of kidney disease causes, with expectations for future treatment development.

(Summary Explanation)

A research team from Kumamoto University's Graduate School of Life Sciences, led by Professor Kazuhito Tomizawa, Associate Professor Takeshi Nakajo, and including special researcher Tomo Nagayoshi and graduate student Yuko Nagata (at the time), has elucidated the mechanism by which reduced function of the tRNA chemical modification enzyme "CDKAL1" exacerbates kidney function. In our bodies, proteins are synthesized based on genetic information. During this process, molecules called "tRNA"¹ and the enzyme "CDKAL1," which adjusts tRNA function through chemical modifications², play crucial roles. This study revealed that when CDKAL1's function is lost, proteins are not synthesized correctly in cells called "podocytes"³ within the kidney. Furthermore, it was shown that the kidney's filtration function is impaired due to the incorrect protein synthesis, leading to a decline in kidney function. This discovery is a significant achievement, leading to a new understanding of the causes of kidney disease. This research is scheduled to be published in the European academic journal "The EMBO Journal" on Saturday, March 28, 2026 (Japan time). This research was supported by grants from the Japan Society for the Promotion of Science (JSPS) and others.

(Explanation)

[Background]

The kidney is an organ that filters unnecessary substances from the blood and excretes them as urine. The "podocyte" cell is central to this "filtration system." Meanwhile, numerous proteins are synthesized daily in the body. In this process, molecules called "tRNA" (Figure 1) act as "carriers" of amino acids, assisting in piecing them together according to the blueprint. tRNA functions normally after receiving chemical modifications³ from specific enzymes. It is known that disruptions in chemical modification mechanisms can lead to disease. Specifically, mutations in the gene for the enzyme "CDKAL1" have been associated with diabetes and kidney disease, but it was unclear whether these kidney diseases were caused by diabetes or developed independently, and the precise mechanism of their onset was not well understood.

[Research Content and Results]

This study revealed that when the enzyme CDKAL1 loses its function, the ability of podocytes, which are responsible for the kidney's filtration function, to correctly incorporate the amino acid lysine into proteins (translation) declines. As a result, essential proteins rich in lysine (especially CD2AP) are not produced sufficiently, leading to impaired podocyte motility and filtration function. Furthermore, in mice lacking CDKAL1, a decline in kidney function was confirmed independently of diabetes. When CD2AP was supplemented in cells lacking CDKAL1, cell function significantly recovered. These results clearly elucidated a new mechanism where CDKAL1 abnormality leads to "decreased synthesis of specific proteins," which in turn causes podocyte dysfunction and exacerbates kidney function (Figure 2).

[Outlook]

This research provides a new perspective that abnormalities in the protein synthesis mechanism can lead to kidney dysfunction. It is expected to contribute to early identification of individuals with CDKAL1 mutations and to initiatives for predicting and preventing the onset and progression of kidney disease in the future. It also opens avenues for developing therapeutic methods to restore reduced lysine translation or novel drug discovery strategies to maintain or enhance podocyte function. Future validation of whether this mechanism operates similarly in humans as it does in disease model mice will advance its application to more practical diagnostic and therapeutic methods.

[Glossary]

※1. tRNA (Transfer RNA, transport RNA): In our bodies, proteins are synthesized based on blueprints written in DNA. In this process, tRNA acts as an "amino acid carrier," helping to link amino acids in the order specified by the blueprint. This mechanism ensures that the proteins needed by the body are accurately produced.

※2. Chemical Modification: A mechanism that adjusts tRNA function by making chemical changes (modifications) to it. These modifications enable proteins to be synthesized more accurately and efficiently. If modifications do not occur properly, errors or reduced efficiency in protein synthesis can arise, potentially causing various diseases.

※3. Podocyte: A cell that constitutes part of the "glomerulus," a filtration unit within the kidney. It works at the forefront of the blood filtration filter. Podocytes spread out like octopus legs to envelop blood vessels, playing a crucial role in excreting small molecules as urine while retaining essential proteins within the body. Damage to these cells can lead to protein in the urine and other declines in kidney function.

(Publication Information)

Paper Title: CDKAL1 dysfunction impairs lysine codon translation in podocytes and accelerates chronic kidney disease

Authors: Yuko Nagata¹, Tomo Nagayoshi¹, Takeshi Nakajo¹, Hitomi Kaneko¹, Shiyose Nishiguchi¹, Yutaka Kakizoe¹, Hiroko Iijima¹, Mitsunori Sakakida¹, Go Masuda², Jun'o Otsuki², Fan-yan Wei³, Yukie Takahashi¹, Koichi Fukuda¹, Hideaki Jinnouchi⁴, Masaki Adachi¹, Ryosuke Yamamura¹, Kohki Matsushita¹, Masataka Adachi¹, Hideki Yokoi¹, Kimitoshi Nakamura¹, Hitoshi Naka², Kazuhito Tomizawa¹

(¹Department of Pharmacology and Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kumamoto University, ²Department of Applied Chemistry, Graduate School of Engineering, Kumamoto University, ³Department of Advanced Medical Science, Institute of Gerontology, Tohoku University, ⁴Jinnai Hospital)

Journal: The EMBO Journal

doi: 10.1038/s44318-026-00759-3

URL: https://link.springer.com/article/10.1038/s44318-026-00759-3

【Contact Information】

＜Regarding Research＞

Kumamoto University Graduate School of Life Sciences

Contact: Professor Kazuhito Tomizawa

Phone: 096-373-5051

e-mail: tomikt@kumamoto-u.ac.jp

＜Regarding Media＞

Kumamoto University General Affairs Department, General Affairs Division, Public Relations Strategy Office

Phone: 096-342-3269

e-mail: sos-koho@jimu.kumamoto-u.ac.jp

Keywords: Kumamoto University, Hospital, Kidney, Protein, Kumamoto University Hospital, Medical Care, Kidney Function, Enzyme, Kidney Disease