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Critical roles of tubular mitochondrial ATP synthase dysfunction in maleic acid-induced acute kidney injury.
Lin, Hugo Y-H; Liang, Chan-Jung; Yang, Ming-Yu; Chen, Phang-Lang; Wang, Tzu-Ming; Chen, Yen-Hua; Shih, Yao-Hsiang; Liu, Wangta; Chiu, Chien-Chih; Chiang, Chih-Kang; Lin, Chang-Shen; Lin, Han-Chen.
Afiliación
  • Lin HY; Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. hugoyl@gap.kmu.edu.tw.
  • Liang CJ; Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. hugoyl@gap.kmu.edu.tw.
  • Yang MY; Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. hugoyl@gap.kmu.edu.tw.
  • Chen PL; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1St Road, Kaohsiung, 80708, Taiwan. hugoyl@gap.kmu.edu.tw.
  • Wang TM; Department of Oral Hygiene, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan.
  • Chen YH; Grander Pharmacy, Kaohsiung, Taiwan.
  • Shih YH; College of Medicine, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
  • Liu W; Department of Biological Chemistry, University of California, Irvine, USA.
  • Chiu CC; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
  • Chiang CK; School of Medicine, Doctoral Program of Clinical and Experimental Medicine, Institute of Biomedical Sciences, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • Lin CS; Department of Anatomy, College of Medicine, Kaohsiung Medical University, 100, Shih-Chuan 1St Road, Kaohsiung, 80708, Taiwan.
  • Lin HC; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Apoptosis ; 29(5-6): 620-634, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38281282
ABSTRACT
Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / ATPasas de Translocación de Protón Mitocondriales / Lesión Renal Aguda / Maleatos / Ratones Endogámicos C57BL / Mitocondrias Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Apoptosis Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apoptosis / ATPasas de Translocación de Protón Mitocondriales / Lesión Renal Aguda / Maleatos / Ratones Endogámicos C57BL / Mitocondrias Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Apoptosis Año: 2024 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Países Bajos