National University Corporation Okayama University
[Okayama University] Discovery of a new renal protective action mechanism of SGLT2 inhibitors
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March 31, 2024 (Reiwa 6) National University Corporation Okayama University https://www.okayama-u.ac.jp/
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GRP78, an intracellular endoplasmic reticulum protein, was found to be secreted into the urine from proximal tubular cells in
diabetes-related kidney disease and spread inflammation to surrounding tubular cells, which was inhibited by canagliflozin.
Canagliflozin inhibited epithelial-mesenchymal transition and interstitial fibrosis in proximal tubular cells in diabetes-associated kidney disease. It was shown that GRP78 may be involved in this mechanism.
Canagliflozin inhibits sugar reabsorption in proximal tubular cells. Due to the decrease in intracellular sugar concentration, GRP78 in the endoplasmic reticulum increased and activated the function of SERCA, which is important for regulating intracellular calcium concentration. It was also found that it improves endoplasmic reticulum function and has a cell protective effect even in kidney disease in people without diabetes.
◆Overview
Lecturer Atsuko Nakashi and Professor Jun Wada of the Department of Nephrology, Diabetes, and Endocrinology at Okayama University Hospital, National University Corporation Okayama University (Headquarters: Kita-ku, Okayama City, President: Yasutomo Nasu) are members of the NPO Japan Kidney Association Kidney Research
Initiative-Japan. (KRI-J) and Mitsubishi Tanabe Pharma Corporation, we discovered a new mechanism of action of canagliflozin, an SGLT2 inhibitor, to suppress the progression of diabetes-related kidney disease.
Canagliflozin changes the protein amount and location of GPR78, suppresses transformation of proximal tubular cells and interstitial fibrosis in diabetes, and even in the absence of diabetes, improves endoplasmic reticulum function and improves cytoplasmic Cells were protected by improving the function of SERCA, a pump that returns excess Ca2+ to the endoplasmic reticulum.
This result was published as a research article in the American Diabetes Association’s journal “Diabetes” on February 23, 2024. This information was released by Okayama University on March 27, 2024. ◆A message from lecturer Atsuko Nakashi
There are multiple factors involved in the progression of
diabetes-related kidney disease, and the course varies. In recent years, SGLT2 inhibitors have become widely used in clinical practice as it has become clear that in addition to lowering blood sugar, they also have the effect of preventing the decline in kidney and heart function. However, the mechanism by which it works remains unclear. This time, we revealed one of the new mechanisms of canagliflozin’s ability to protect the kidneys. I would like to continue doing basic research that will benefit clinical medicine and patients. We would like to express our deepest gratitude to everyone involved in the research.
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◆ Paper information paper Name: GRP78 Contributes to the Beneficial Effects of SGLT2 Inhibitors on Proximal Tubular Cells in DKD (The effectiveness of SGLT2 inhibitors in diabetes-related kidney disease is mediated by GRP78 in proximal tubular cells) Paper: Diabetes Author: Atsuko Nakatsuka, Satoshi , Jun WadaD O I: 10.2337/db23-0581U R L:
https://diabetesjournals.org/diabetes/article-abstract/doi/10.2337/db23-0581/154287/GRP78-contributes-to-the-beneficial-effects-of?redirectedFrom=fulltext ◆Research funding This research is a joint venture between the NPO Japan Kidney Association and Mitsubishi Tanabe Pharma, and is supported by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (Grant-in-Aid for Scientific Research C/23K07673, Research Representative: Nakamura This work was carried out with the support of Atsuko Tsukasa.
◆About detailed research content
Discovered a new renal protective action mechanism of SGLT2 inhibitors https://www.okayama-u.ac.jp/up_load_files/press_r5/press20240327-6.pdf ◆Reference
・Okayama University Faculty of Medicine, Department of Medicine, Dentistry and Pharmaceutical Sciences (Medicine) Department of Nephrology, Immunology, Endocrinology and Metabolism
https://daisan.med.okayama-u.ac.jp/
・Okayama University Hospital
https://www.okayama-u.ac.jp/user/hospital/
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◆Contact information for this matter
Atsuko Nakatsuka, Lecturer, Department of Nephrology, Diabetes, and Endocrinology, Okayama University
Okayama University Shikata Campus, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama 700-8558
TEL: 086-235-7235 FAX: 086-222-5214
https://daisan.med.okayama-u.ac.jp/
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