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SGLT2i-Triggered hyperglycosuria Unveils CDKN2A-Driven distal tubular senescence and EMT, Fueling renal fibrosis.

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Τίτλος: SGLT2i-Triggered hyperglycosuria Unveils CDKN2A-Driven distal tubular senescence and EMT, Fueling renal fibrosis.
Συγγραφείς: Chen Y; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Zheng SC; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Bai YF; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Deng WZ; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Gong N; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Fu YF; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Zhang ZY; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Chen XM; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China., Hong Q; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China. Electronic address: hongquan@301hospital.com.cn., Sun XF; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China. Electronic address: xfssun@126.com.
Πηγή: Biochemical pharmacology [Biochem Pharmacol] 2026 Aug; Vol. 250 (Pt 1), pp. 117942. Date of Electronic Publication: 2026 Mar 31.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
Imprint Name(s): Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
Ιατρικοί όροι (MeSH): Epithelial-Mesenchymal Transition*/drug effects , Epithelial-Mesenchymal Transition*/physiology , Cellular Senescence*/drug effects , Cellular Senescence*/physiology , Sodium-Glucose Transporter 2 Inhibitors*/toxicity , Cyclin-Dependent Kinase Inhibitor p16*/metabolism , Kidney Tubules, Distal*/drug effects , Kidney Tubules, Distal*/metabolism , Kidney Tubules, Distal*/pathology, Fibrosis/metabolism ; Fibrosis/chemically induced ; Benzhydryl Compounds/toxicity ; Glucosides/toxicity ; Glucosides/pharmacology ; Animals ; Mice, Inbred C57BL ; Mice ; Male ; Sodium-Glucose Transporter 2
Περίληψη: SGLT2 inhibitors are widely recommended by clinical guidelines for managing diabetes, cardiovascular, and kidney diseases. High glucose induces proximal tubular epithelial cell senescence and epithelial-mesenchymal transition (EMT), promoting renal interstitial fibrosis. However, the impact of SGLT2 inhibitor-induced hyperglucosuria on distal tubular cell biology remains unreported. C57BL/6 or db/db mice were administered empagliflozin via oral gavage for 4 weeks. Tissues were collected post-intervention to assess the immediate effects on distal tubular cell senescence and EMT. After treatment cessation, C57BL/6 and db/db mice were maintained for another 24 and 11 weeks respectively to investigate subsequent effects. In vitro, mouse distal convoluted tubule (mDCT) cells were stimulated with high glucose to verify mechanisms of glucose-induced senescence and EMT. Empagliflozin induced hyperglucosuria that persisted post-cessation. In C57BL/6 mice, immediate effects led to senescence marked by CDKN1A upregulation and EMT in distal tubular cells. Twenty-four weeks post-cessation, these cells exhibited senescence with co-upregulation of CDKN2A and CDKN1A, EMT progression, and renal interstitial fibrosis. In db/db mice, immediate effects did not exacerbate senescence or EMT, but 11 weeks post-cessation aggravated senescence, EMT progression, and renal interstitial fibrosis. In vitro, high glucose promoted reactive oxygen species (ROS) generation, exacerbated DNA damage, and induced mDCT cell senescence and EMT by upregulating CDKN2A. This study first demonstrates that persistent SGLT2 inhibitor-induced hyperglucosuria drives distal tubular cell senescence, EMT, and renal interstitial fibrosis in wild-type and db/db mice, providing foundational evidence for a more comprehensive understanding of these drugs.
(Copyright © 2026 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Contributed Indexing: Keywords: Cellular Senescence; Epithelial-Mesenchymal Transition; Kidney Tubules, Distal; Sodium-Glucose Transporter 2Inhibitors
Substance Nomenclature: 0 (Sodium-Glucose Transporter 2 Inhibitors)
0 (Cyclin-Dependent Kinase Inhibitor p16)
HDC1R2M35U (empagliflozin)
0 (Benzhydryl Compounds)
0 (Cdkn2a protein, mouse)
0 (Glucosides)
0 (Slc5a2 protein, mouse)
0 (Sodium-Glucose Transporter 2)
Entry Date(s): Date Created: 20260404 Date Completed: 20260610 Latest Revision: 20260610
Update Code: 20260610
DOI: 10.1016/j.bcp.2026.117942
PMID: 41933739
Βάση Δεδομένων: MEDLINE
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  Data: SGLT2i-Triggered hyperglycosuria Unveils CDKN2A-Driven distal tubular senescence and EMT, Fueling renal fibrosis.
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  Data: <searchLink fieldCode="AU" term="%22Chen+Y%22">Chen Y</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China.<br /><searchLink fieldCode="AU" term="%22Zheng+SC%22">Zheng SC</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China.<br /><searchLink fieldCode="AU" term="%22Bai+YF%22">Bai YF</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China.<br /><searchLink fieldCode="AU" term="%22Deng+WZ%22">Deng WZ</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; 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Medical School of Chinese PLA, Beijing 100853, China.<br /><searchLink fieldCode="AU" term="%22Zhang+ZY%22">Zhang ZY</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China.<br /><searchLink fieldCode="AU" term="%22Chen+XM%22">Chen XM</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China.<br /><searchLink fieldCode="AU" term="%22Hong+Q%22">Hong Q</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China. Electronic address: hongquan@301hospital.com.cn.<br /><searchLink fieldCode="AU" term="%22Sun+XF%22">Sun XF</searchLink>; Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Medical Devices and Integrated Traditional Chinese and Western Drug Development for Severe Kidney Diseases, Beijing Key Laboratory of Digital Intelligent TCM for the Prevention and Treatment of Pan-vascular Diseases, Key Disciplines of National Administration of Traditional Chinese Medicine(zyyzdxk-2023310), Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China. Electronic address: xfssun@126.com.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: SGLT2 inhibitors are widely recommended by clinical guidelines for managing diabetes, cardiovascular, and kidney diseases. High glucose induces proximal tubular epithelial cell senescence and epithelial-mesenchymal transition (EMT), promoting renal interstitial fibrosis. However, the impact of SGLT2 inhibitor-induced hyperglucosuria on distal tubular cell biology remains unreported. C57BL/6 or db/db mice were administered empagliflozin via oral gavage for 4 weeks. Tissues were collected post-intervention to assess the immediate effects on distal tubular cell senescence and EMT. After treatment cessation, C57BL/6 and db/db mice were maintained for another 24 and 11 weeks respectively to investigate subsequent effects. In vitro, mouse distal convoluted tubule (mDCT) cells were stimulated with high glucose to verify mechanisms of glucose-induced senescence and EMT. Empagliflozin induced hyperglucosuria that persisted post-cessation. In C57BL/6 mice, immediate effects led to senescence marked by CDKN1A upregulation and EMT in distal tubular cells. Twenty-four weeks post-cessation, these cells exhibited senescence with co-upregulation of CDKN2A and CDKN1A, EMT progression, and renal interstitial fibrosis. In db/db mice, immediate effects did not exacerbate senescence or EMT, but 11 weeks post-cessation aggravated senescence, EMT progression, and renal interstitial fibrosis. In vitro, high glucose promoted reactive oxygen species (ROS) generation, exacerbated DNA damage, and induced mDCT cell senescence and EMT by upregulating CDKN2A. This study first demonstrates that persistent SGLT2 inhibitor-induced hyperglucosuria drives distal tubular cell senescence, EMT, and renal interstitial fibrosis in wild-type and db/db mice, providing foundational evidence for a more comprehensive understanding of these drugs.<br /> (Copyright © 2026 Elsevier Inc. All rights reserved.)
– Name: Abstract
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  Data: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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  Data: <i>Keywords: </i>Cellular Senescence; Epithelial-Mesenchymal Transition; Kidney Tubules, Distal; Sodium-Glucose Transporter 2Inhibitors
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  Data: 0 (Sodium-Glucose Transporter 2 Inhibitors)<br />0 (Cyclin-Dependent Kinase Inhibitor p16)<br />HDC1R2M35U (empagliflozin)<br />0 (Benzhydryl Compounds)<br />0 (Cdkn2a protein, mouse)<br />0 (Glucosides)<br />0 (Slc5a2 protein, mouse)<br />0 (Sodium-Glucose Transporter 2)
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        Text: English
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        StartPage: 117942
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      – SubjectFull: Fibrosis metabolism
        Type: general
      – SubjectFull: Fibrosis chemically induced
        Type: general
      – SubjectFull: Benzhydryl Compounds toxicity
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      – SubjectFull: Kidney Tubules, Distal pathology
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      – TitleFull: SGLT2i-Triggered hyperglycosuria Unveils CDKN2A-Driven distal tubular senescence and EMT, Fueling renal fibrosis.
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            – Type: issue
              Value: Pt 1
          Titles:
            – TitleFull: Biochemical pharmacology
              Type: main
ResultId 1