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KCa3.1 Mediates Dysregulation of Mitochondrial Quality Control in Diabetic Kidney Disease.
Huang, Chunling; Yi, Hao; Shi, Ying; Cao, Qinghua; Shi, Yin; Cheng, Delfine; Braet, Filip; Chen, Xin-Ming; Pollock, Carol A.
Affiliation
  • Huang C; Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
  • Yi H; Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
  • Shi Y; Division of Nephrology, School of Medicine, Stanford University, Stanford, CA, United States.
  • Cao Q; Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
  • Shi Y; Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
  • Cheng D; Discipline of Anatomy and Histology, School of Medical Sciences, Faculty of Medicine and Health, The Bosch Institute, University of Sydney, Sydney, NSW, Australia.
  • Braet F; Discipline of Anatomy and Histology, School of Medical Sciences, Faculty of Medicine and Health, The Bosch Institute, University of Sydney, Sydney, NSW, Australia.
  • Chen XM; Australian Centre for Microscopy and Microanalysis, University of Sydney, Sydney, NSW, Australia.
  • Pollock CA; Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
Front Cell Dev Biol ; 9: 573814, 2021.
Article in En | MEDLINE | ID: mdl-33681190
ABSTRACT
Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease. Mitochondrial quality control is primarily mediated by mitochondrial turnover and repair through mitochondrial fission/fusion and mitophagy. We have previously shown that blockade of the calcium-activated potassium channel KCa3.1 ameliorates diabetic renal fibrosis. However, the mechanistic link between KCa3.1 and mitochondrial quality control in diabetic kidney disease is not yet known. Transforming growth factor ß1 (TGF-ß1) plays a central role in diabetic kidney disease. Recent studies indicate an emerging role of TGF-ß1 in the regulation of mitochondrial function. However, the molecular mechanism mediating mitochondrial quality control in response to TGF-ß1 remains limited. In this study, mitochondrial function was assessed in TGF-ß1-exposed renal proximal tubular epithelial cells (HK2 cells) transfected with scrambled siRNA or KCa3.1 siRNA. In vivo, diabetes was induced in KCa3.1+/+ and KCa3.1-/- mice by low-dose streptozotocin (STZ) injection. Mitochondrial fission/fusion-related proteins and mitophagy markers, as well as BCL2 interacting protein 3 (BNIP3) (a mitophagy regulator) were examined in HK2 cells and diabetic mice kidneys. The in vitro results showed that TGF-ß1 significantly inhibited mitochondrial ATP production rate and increased mitochondrial ROS (mtROS) production when compared to control, which was normalized by KCa3.1 gene silencing. Increased fission and suppressed fusion were found in both TGF-ß1-treated HK2 cells and diabetic mice, which were reversed by KCa3.1 deficiency. Furthermore, our results showed that mitophagy was inhibited in both in vitro and in vivo models of diabetic kidney disease. KCa3.1 deficiency restored abnormal mitophagy by inhibiting BNIP3 expression in TGF-ß1-induced HK2 cells as well as in the diabetic mice. Collectively, these results indicate that KCa3.1 mediates the dysregulation of mitochondrial quality control in diabetic kidney disease.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: Front Cell Dev Biol Year: 2021 Document type: Article Affiliation country: Australia
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: Front Cell Dev Biol Year: 2021 Document type: Article Affiliation country: Australia