FoxO3 activation in hypoxic tubules prevents chronic kidney disease

J Clin Invest. 2019 Mar 26;129(6):2374-2389. doi: 10.1172/JCI122256.


Acute kidney injury (AKI) can lead to chronic kidney disease (CKD) if injury is severe and/or repair is incomplete. However, the pathogenesis of CKD following renal ischemic injury is not fully understood. Capillary rarefaction and tubular hypoxia are common findings during the AKI to CKD transition. We investigated the tubular stress response to hypoxia and demonstrated that a stress responsive transcription factor, FoxO3, was regulated by prolyl hydroxylase. Hypoxia inhibited FoxO3 prolyl hydroxylation and FoxO3 degradation, thus leading to FoxO3 accumulation and activation in tubular cells. Hypoxia-activated Hif-1α contributed to FoxO3 activation and functioned to protect kidneys, as tubular deletion of Hif-1α decreased hypoxia-induced FoxO3 activation, and resulted in more severe tubular injury and interstitial fibrosis following ischemic injury. Strikingly, tubular deletion of FoxO3 during the AKI to CKD transition aggravated renal structural and functional damage leading to a more profound CKD phenotype. We showed that tubular deletion of FoxO3 resulted in decreased autophagic response and increased oxidative injury, which may explain renal protection by FoxO3. Our study indicates that in the hypoxic kidney, stress responsive transcription factors can be activated for adaptions to counteract hypoxic insults, thus attenuating CKD development.

Keywords: Autophagy; Cell Biology; Nephrology; hypoxia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control
  • Animals
  • Autophagic Cell Death*
  • Cell Hypoxia / genetics
  • Fibrosis
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / metabolism*
  • Kidney Tubules / metabolism*
  • Kidney Tubules / pathology
  • Mice
  • Mice, Transgenic
  • Oxidative Stress*
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism
  • Renal Insufficiency, Chronic / pathology
  • Renal Insufficiency, Chronic / prevention & control*


  • Forkhead Box Protein O3
  • FoxO3 protein, mouse