Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease
Objectives Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease. The precise molecular mechanism of ferroptosis, an iron-dependent and non-apoptotic form of regulated cell death, remains poorly understood in DKD, as does the impact of sodium-glucose cotransporter 2 inhibitors (...
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Taylor & Francis Group
2025-12-01
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| Series: | Redox Report |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/13510002.2025.2528334 |
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| author | Yi-Chun Tsai Jiun-Chi Huang Ping-Shaou Yu Mei-Chuan Kuo Ling-Yu Wu Wei-An Chang Shang-Jyh Hwang Ya-Ling Hsu |
| author_facet | Yi-Chun Tsai Jiun-Chi Huang Ping-Shaou Yu Mei-Chuan Kuo Ling-Yu Wu Wei-An Chang Shang-Jyh Hwang Ya-Ling Hsu |
| author_sort | Yi-Chun Tsai |
| collection | DOAJ |
| description | Objectives Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease. The precise molecular mechanism of ferroptosis, an iron-dependent and non-apoptotic form of regulated cell death, remains poorly understood in DKD, as does the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on ferroptosis-mediated DKD.Methods This study used bulk RNA sequencing, in vitro and in vivo models, and human kidney samples to explore the molecular mechanisms involved in oxidative stress and ferroptosis in the proximal tubule (PT) of DKD.Results High glucose (HG) induced features of ferroptosis in HK-2 cells. Transcriptome analysis of primary PT cells from diabetic patients indicated that glutathione cysteine ligase modifier (GCLM) subunit is involved in ferroptosis. Immunohistochemical staining revealed that db/db mice and diabetic patients had lower glutathione peroxidase 4 and GCLM expression in the PT. Suppression of GCLM enhanced ferroptosis, whereas GCLM overexpression mitigated HG-induced ferroptosis in HK-2 cells. Antioxidants reduced oxidative stress and ferroptosis in both in vitro and in vivo models of DKD. Furthermore, SGLT2i attenuated PT ferroptosis in these models and improved DKD by increasing GCLM expression.Conclusion SGLT2i reduced ferroptosis in PT by boosting GCLM expression, thereby slowing DKD progression, revealing that GCLM has the potential against DKD. |
| format | Article |
| id | doaj-art-c6e545feed804442b4b09cb760dba54c |
| institution | Kabale University |
| issn | 1351-0002 1743-2928 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Redox Report |
| spelling | doaj-art-c6e545feed804442b4b09cb760dba54c2025-08-20T03:58:40ZengTaylor & Francis GroupRedox Report1351-00021743-29282025-12-0130110.1080/13510002.2025.2528334Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney diseaseYi-Chun Tsai0Jiun-Chi Huang1Ping-Shaou Yu2Mei-Chuan Kuo3Ling-Yu Wu4Wei-An Chang5Shang-Jyh Hwang6Ya-Ling Hsu7School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanSchool of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDivision of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanDivision of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDivision of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanDivision of Nephrology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanDrug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, TaiwanObjectives Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease. The precise molecular mechanism of ferroptosis, an iron-dependent and non-apoptotic form of regulated cell death, remains poorly understood in DKD, as does the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on ferroptosis-mediated DKD.Methods This study used bulk RNA sequencing, in vitro and in vivo models, and human kidney samples to explore the molecular mechanisms involved in oxidative stress and ferroptosis in the proximal tubule (PT) of DKD.Results High glucose (HG) induced features of ferroptosis in HK-2 cells. Transcriptome analysis of primary PT cells from diabetic patients indicated that glutathione cysteine ligase modifier (GCLM) subunit is involved in ferroptosis. Immunohistochemical staining revealed that db/db mice and diabetic patients had lower glutathione peroxidase 4 and GCLM expression in the PT. Suppression of GCLM enhanced ferroptosis, whereas GCLM overexpression mitigated HG-induced ferroptosis in HK-2 cells. Antioxidants reduced oxidative stress and ferroptosis in both in vitro and in vivo models of DKD. Furthermore, SGLT2i attenuated PT ferroptosis in these models and improved DKD by increasing GCLM expression.Conclusion SGLT2i reduced ferroptosis in PT by boosting GCLM expression, thereby slowing DKD progression, revealing that GCLM has the potential against DKD.https://www.tandfonline.com/doi/10.1080/13510002.2025.2528334Sodium–glucose cotransporter 2 inhibitorproximal tubuleoxidative stressferroptosisglutathione cysteine ligase modifierdiabetic kidney disease |
| spellingShingle | Yi-Chun Tsai Jiun-Chi Huang Ping-Shaou Yu Mei-Chuan Kuo Ling-Yu Wu Wei-An Chang Shang-Jyh Hwang Ya-Ling Hsu Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease Redox Report Sodium–glucose cotransporter 2 inhibitor proximal tubule oxidative stress ferroptosis glutathione cysteine ligase modifier diabetic kidney disease |
| title | Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease |
| title_full | Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease |
| title_fullStr | Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease |
| title_full_unstemmed | Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease |
| title_short | Sodium–glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier-mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease |
| title_sort | sodium glucose cotransporter 2 inhibitors ameliorate glutathione cysteine ligase modifier mediated oxidative stress and subsequent ferroptosis in proximal tubules of diabetic kidney disease |
| topic | Sodium–glucose cotransporter 2 inhibitor proximal tubule oxidative stress ferroptosis glutathione cysteine ligase modifier diabetic kidney disease |
| url | https://www.tandfonline.com/doi/10.1080/13510002.2025.2528334 |
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