New Cause of Kidney Disease Worsening Discovered: Abnormalities in the 'Protein Synthesis Mechanism' Cause Declined Renal Function

(Points) - Discovered that 'CDKAL1,' an enzyme that adjusts accurate protein synthesis in the body, has a new function in maintaining kidney activity. - When the function of this enzyme weakens, the 'filter function' of the kidney is impaired. - Leads to an understanding of a new cause of kidney disease, with expectations for future treatment development.

(Summary Description) A research team led by Professor Kazuhito Tomizawa, Specially Appointed Lecturer Tomu Nagayoshi, Graduate Student Yuko Nagata (at the time), and Associate Professor Takeshi Chujo of the Graduate School of Life Sciences, Kumamoto University, has clarified the mechanism by which the functional decline of the enzyme 'CDKAL1,' which chemically modifies tRNA, worsens kidney function.

In our bodies, proteins are created based on genetic information. Molecules called 'tRNA' (*1) and the enzyme 'CDKAL1,' which adjusts tRNA function by chemical modification (*2), play crucial roles in this process.

This study revealed that when CDKAL1 ceases to function, proteins are no longer correctly produced in cells called 'podocytes' (*3) within the kidney. Furthermore, it was shown that the failure to produce proteins correctly impairs the kidney's filter function, leading to declined renal function. This discovery is a significant achievement leading to a new understanding of the causes of kidney disease.

The results of this research are scheduled to be published in the European academic journal 'The EMBO Journal' on Saturday, March 28, 2026 (Japan Time). This research was conducted with support from the Japan Society for the Promotion of Science's Grants-in-Aid for Scientific Research, among others.

(Description) [Background] The kidney is an organ that filters unnecessary substances from the blood and excretes them as urine. 'Podocytes' are the central cells of this 'filtration device.'

Meanwhile, many proteins are produced in the body every day. In that process, tRNA molecules (Fig. 1) transport amino acids and assist in protein synthesis. tRNA performs its normal function through chemical modification (*2) from specialized enzymes. It was known that disruptions in this chemical modification mechanism lead to diseases. In particular, mutations in the blueprint (gene) of the 'CDKAL1' enzyme were known to be related to diabetes and kidney disease, but it was not well understood whether this kidney disease was caused by diabetes or developed independently of it, nor was the specific mechanism clearly known.

[Research Content and Results] This study clarified that when the CDKAL1 enzyme fails to work, the ability to correctly incorporate lysine, a type of amino acid, into proteins (translation) decreases in the podocytes responsible for the kidney's filter function. As a result, important proteins containing high amounts of lysine (especially CD2AP) are not sufficiently produced, leading to a decline in podocyte migration ability and filter function. Furthermore, a decline in renal function was confirmed in CDKAL1-deficient mice independently of diabetes, and it was shown that cell function recovered significantly by supplementing CD2AP in CDKAL1-deficient cells. These results clearly established a new mechanism where CDKAL1 abnormalities cause a 'decrease in the synthesis of specific proteins,' leading to renal function worsening through podocyte dysfunction (Fig. 2).

[Outlook] Since this study provided a new perspective that abnormalities in the protein synthesis mechanism lead to declined renal function, it is hoped that in the future, individuals with CDKAL1 mutations can be identified early to predict and prevent the onset and progression of kidney disease.