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UCP2-dependent improvement of mitochondrial dynamics protects against acute kidney injury.

Abstract
Acute kidney injury (AKI) is a public health concern, with high morbidity and mortality rates in hospitalized patients and because survivors have an increased risk of progression to chronic kidney disease. Mitochondrial damage is the critical driver of AKI-associated dysfunction and loss of tubular epithelial cells; however, the pathways that mediate these events are poorly defined. Here, in murine ischemia/reperfusion (I/R)-induced AKI, we determined that mitochondrial damage is associated with the level of renal uncoupling protein 2 (UCP2). In hypoxia-damaged proximal tubular cells, a disruption of mitochondrial dynamics demonstrated by mitochondrial fragmentation and disturbance between fusion and fission was clearly indicated. Ucp2-deficient mice (knockout mice) with I/R injury experienced more severe AKI and mitochondrial fragmentation than wild-type mice. Moreover, genetic or pharmacological treatment increased UCP2 expression, improved renal function, reduced tubular injury and limited mitochondrial fission. In cultured proximal tubular epithelial cells, hypoxia-induced mitochondrial fission was exacerbated in cells with UCP2 deletion, whereas an increase in UCP2 ameliorated the hypoxia-induced disturbance of the balance between mitochondrial fusion and fission. Furthermore, results following modulation of UCP2 suggested it has a role in preserving mitochondrial integrity by preventing loss of membrane potential and reducing subsequent mitophagy. Taken together, our results indicate that UCP2 is protective against AKI and suggest that enhancing UCP2 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
AuthorsNan Qin, Ting Cai, Qingqing Ke, Qi Yuan, Jing Luo, Xiaoming Mao, Lei Jiang, Hongdi Cao, Ping Wen, Ke Zen, Yang Zhou, Junwei Yang
JournalThe Journal of pathology (J Pathol) Vol. 247 Issue 3 Pg. 392-405 (03 2019) ISSN: 1096-9896 [Electronic] England
PMID30426490 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Chemical References
  • Ucp2 protein, mouse
  • Uncoupling Protein 2
  • Protein Kinases
  • PTEN-induced putative kinase
Topics
  • Acute Kidney Injury (etiology, metabolism, pathology, prevention & control)
  • Animals
  • Cell Hypoxia (physiology)
  • Cells, Cultured
  • Kidney Tubules, Proximal (ultrastructure)
  • Male
  • Membrane Potential, Mitochondrial (physiology)
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Electron
  • Mitochondria (physiology)
  • Mitochondrial Dynamics (physiology)
  • Mitophagy (physiology)
  • Protein Kinases (physiology)
  • Reperfusion Injury (complications)
  • Uncoupling Protein 2 (deficiency, genetics, metabolism, physiology)
  • Up-Regulation (physiology)

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