GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition
Abstract Semaglutide (Smg), a GLP‐1 receptor agonist (GLP‐1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β‐Klotho (KLB) as the critical target res...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202409781 |
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| author | Shasha Tian Saijun Zhou Weixi Wu Yao lin Tongdan Wang Haizhen Sun A‐Shan‐Jiang A‐Ni‐Wan Yaru Li Chongyang Wang Xiaogang Li Pei Yu Yanjun Zhao |
| author_facet | Shasha Tian Saijun Zhou Weixi Wu Yao lin Tongdan Wang Haizhen Sun A‐Shan‐Jiang A‐Ni‐Wan Yaru Li Chongyang Wang Xiaogang Li Pei Yu Yanjun Zhao |
| author_sort | Shasha Tian |
| collection | DOAJ |
| description | Abstract Semaglutide (Smg), a GLP‐1 receptor agonist (GLP‐1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β‐Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK‐2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP‐response element‐binding protein (CREB). Subsequently, the adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP‐1RAs and KLB targeting as promising therapeutic approaches for DKD management. |
| format | Article |
| id | doaj-art-f78047ae81f94b3b9296bb82aade7ea7 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-f78047ae81f94b3b9296bb82aade7ea72025-01-29T09:50:19ZengWileyAdvanced Science2198-38442025-01-01124n/an/a10.1002/advs.202409781GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis InhibitionShasha Tian0Saijun Zhou1Weixi Wu2Yao lin3Tongdan Wang4Haizhen Sun5A‐Shan‐Jiang A‐Ni‐Wan6Yaru Li7Chongyang Wang8Xiaogang Li9Pei Yu10Yanjun Zhao11NHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaNHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaNHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaNHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaNHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaNHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaNHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaSchool of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, Faculty of Medicine Tianjin UniversityTianjin 300072 ChinaSchool of Life Sciences Peking UniversityBeijing 100871 ChinaDepartment of Internal Medicine Mayo Clinic Rochester MN 55901 USANHC Key Laboratory of Hormones and Development, Chu Hsien‐I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Key Laboratory of Metabolic Diseases Tianjin Medical UniversityTianjin 300134 ChinaSchool of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, Faculty of Medicine Tianjin UniversityTianjin 300072 ChinaAbstract Semaglutide (Smg), a GLP‐1 receptor agonist (GLP‐1RA), shows renal protective effects in patients with diabetic kidney disease (DKD). However, the exact underlying mechanism remains elusive. This study employs transcriptome sequencing and identifies β‐Klotho (KLB) as the critical target responsible for the role of Smg in kidney protection. Smg treatment alleviates diabetic kidney injury by inhibiting ferroptosis in patients, animal models, and HK‐2 cells. Notably, Smg treatment significantly increases the mRNA expression of KLB through the activation of the cyclic adenosine monophosphate (cAMP) signaling pathway, specifically through the phosphorylation of protein kinase A (PKA) and cAMP‐response element‐binding protein (CREB). Subsequently, the adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway is activated, reprograming the key metabolic processes of ferroptosis such as iron metabolism, fatty acid synthesis, and the antioxidant response against lipid peroxidation. Suppression of ferroptosis by Smg further attenuates renal inflammation and fibrosis. This work highlights the potential of GLP‐1RAs and KLB targeting as promising therapeutic approaches for DKD management.https://doi.org/10.1002/advs.202409781diabetic kidney diseaseferroptosisGLP‐1 receptor agonistsemaglutideβ‐Klotho |
| spellingShingle | Shasha Tian Saijun Zhou Weixi Wu Yao lin Tongdan Wang Haizhen Sun A‐Shan‐Jiang A‐Ni‐Wan Yaru Li Chongyang Wang Xiaogang Li Pei Yu Yanjun Zhao GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition Advanced Science diabetic kidney disease ferroptosis GLP‐1 receptor agonist semaglutide β‐Klotho |
| title | GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition |
| title_full | GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition |
| title_fullStr | GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition |
| title_full_unstemmed | GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition |
| title_short | GLP‐1 Receptor Agonists Alleviate Diabetic Kidney Injury via β‐Klotho‐Mediated Ferroptosis Inhibition |
| title_sort | glp 1 receptor agonists alleviate diabetic kidney injury via β klotho mediated ferroptosis inhibition |
| topic | diabetic kidney disease ferroptosis GLP‐1 receptor agonist semaglutide β‐Klotho |
| url | https://doi.org/10.1002/advs.202409781 |
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