Abstract
In March 2024, kidney injury sometimes accompanied with Fanconi syndrome caused by a supplement made from red yeast rice (Beni-koji Choleste-Help) were reported in Japan. By November 24, 2024, 2,628 people had visited medical facilities, resulting in a social problem. Many patients still have a decline in eGFR. The previous report, however, did not indicate anything other than that puberulic acid which newly identified nephrotoxicity was contained in toxic lots. The pathophysiology of those nephropathies should be determined. Here, we discovered that mitochondrial dysfunction in renal proximal tubular epithelial cells plays a pivotal role in them. A patient renal biopsy sample showed Kidney Injury Molecule-1 (KIM-1) expression in proximal tubules surrounded by activated myofibroblasts, indicating acute tubular damage and interstitial fibrosis associated with injured tubules. Mice treated with the toxic lot of Choleste-Help and puberulic acid showed kidney injury with Fanconi syndrome-like urinary findings. Pathological sections showed tubular necrosis and interstitial fibrosis. RNA-seq on whole kidneys of those mice presented the renal damage caused by Choleste-Help and puberulic acid produced similar RNA patterns, indicating puberulic acid is a causative agent. Gene Ontology (GO) analysis comparing the normal and toxic lot revealed downregulation of mitochondrial-related pathways. Puberulic acid also showed toxicity on human primary epithelial cells and tubular organoids. In vitro experiments with human primary cells revealed that it causes mitochondrial damage at first and leads to cell death, mainly necrosis. Thus, puberulic and a toxic lot of Choleste-Help cause direct mitochondrial damage on tubular epithelial cells, followed by necrosis.
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Translational Statement Our research revealed the pathophysiology of puberilic acid nephropathy, which suffers many patients. And we used not only animal models, but human kidney-derived primary cultured tubular epithelial cells and its 3D organoids, which are ones of the closest models of human body.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This study was funded byLeading Initiative for Excellent Young Researchers (LEADER) from Ministry of Education, Culture, Sports, Science and Technology (to Y.M.), Grant-in-Aid for Research Activity Start-up (22K20881) and Grand-in-Aid for Scientific Research (B) (24K03249) from Japan Society for the Promotion of Science (to Y.M.), Innovation Idea Contest from Tokyo Medical and Dental University (TMDU) (in 2022 to Y.M. and in 2023 to Y.N.), Next Generation Researcher Training Unit from TMDU (to Y.M.) and Priority Research Areas Grant from TMDU (to Y.M.), Research Grant from Uehara Memorial Foundation (to Y.M.), Research Grant (Lifestyle-related diseases) from MSD Life Science Foundation (to Y.M.), Medical Research Grant from Takeda Science Foundation (to Y.M.), Academic Support from Bayer Yakuhin, Ltd. (to Y.M.), and Japan Agency for Medical Research and Development (AMED) (24gm6910017h0001) (to E.S.).
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethics committee/IRB of Institute of Science Tokyo, Kidney Disease and Transplant Center, Shonan Kamakura General Hospital and Japanese Red Cross Musashino Hospital gave ethical approval for this work
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Data Availability
All data produced in the present study are available upon reasonable request to the authors
