Dynamin-Related Protein 1 Deficiency Promotes Recovery from AKI

J Am Soc Nephrol. 2018 Jan;29(1):194-206. doi: 10.1681/ASN.2017060659. Epub 2017 Oct 30.


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 β-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.

Keywords: acute renal failure; chronic kidney disease; fibrosis; ischemia-reperfusion; mitochondria; proximal tubule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / metabolism*
  • Acute Kidney Injury / etiology
  • Acute Kidney Injury / genetics*
  • Animals
  • Apoptosis / genetics
  • Disease Progression
  • Dynamins / antagonists & inhibitors
  • Dynamins / genetics*
  • Fibrosis
  • Kidney Tubules, Proximal / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Dynamics / genetics
  • Nephritis / etiology
  • Nephritis / genetics
  • Oxidative Stress / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Renal Insufficiency, Chronic / genetics*
  • Reperfusion Injury / complications
  • Signal Transduction


  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Dnm1l protein, mouse
  • Dynamins
  • 3-Hydroxybutyric Acid