Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 29, Issue 1, Pages 194-206Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2017060659
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [F32DK108563, T32DK72922]
- American Society of Nephrology Ben Lipps Fellowship Program [DK091444, DK107941, R01 062324, R01 085259]
- National Institutes of Health [1S10RR026799-01, 1S10RR021017-01]
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The proximal tubule epithelium relies on mitochondrial function for energy, rendering the kidney highly susceptible to ischemic AKI. Dynamin-related protein 1 (DRP1), a mediator of mitochondrial fission, regulates mitochondrial function; however, the cell-specific and temporal role of DRP1 in AKI in vivo is unknown. Using genetic murine models, we found that proximal tubule-specific deletion of Drp1 prevented the renal ischemia-reperfusion-induced kidney injury, inflammation, and programmed cell death observed in wild-type mice and promoted epithelial recovery, which associated with activation of the renoprotective beta-hydroxybutyrate signaling pathway. Loss of DRP1 preserved mitochondrial structure and reduced oxidative stress in injured kidneys. Lastly, proximal tubule deletion of DRP1 after ischemia-reperfusion injury attenuated progressive kidney injury and fibrosis. These results implicate DRP1 and mitochondrial dynamics as an important mediator of AKI and progression to fibrosis and suggest that DRP1 may serve as a therapeutic target for AKI.
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