FoxO3 activation in hypoxic tubules prevents chronic kidney disease
Ling Li, … , Qais Al-Awqati, Fangming Lin
Ling Li, … , Qais Al-Awqati, Fangming Lin
Published March 26, 2019
Citation Information: J Clin Invest. 2019;129(6):2374-2389. https://doi.org/10.1172/JCI122256.
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Research Article Cell biology Nephrology Article has an altmetric score of 10

FoxO3 activation in hypoxic tubules prevents chronic kidney disease

Abstract

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 (PHD). Hypoxia inhibited FoxO3 prolyl hydroxylation and FoxO3 degradation, 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 much more profound CKD phenotype. We show 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.

Authors

Ling Li, Huimin Kang, Qing Zhang, Vivette D. D’Agati, Qais Al-Awqati, Fangming Lin

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Figure 7

Loss of FoxO3 results in more severe oxidative injury.

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Loss of FoxO3 results in more severe oxidative injury. (A) Tubular FoxO3...
(A) Tubular FoxO3 was deleted from day 8 to day 21 following a 35-minute left kidney IRI and right nephrectomy. Kidneys were analyzed 4 weeks after IRI. Lower levels of SOD2 protein were detected in FoxO3tub compared with levels in FoxO3ctl mouse kidneys. n = 4. *P < 0.05, comparing FoxO3tub with FoxO3ctl; 2-tailed Student’s t test (B) Left and middle panels: Primary cultures were isolated from normal kidneys of mice treated with doxycycline or vehicle for 2 weeks (FoxO3tub or FoxO3ctl mice) and exposed to 1% O2 for 1 hour prior to incubation with MitoSOX Red or DHE. Mitochondrial superoxide levels indicated by MitoSOX Red (left panel) showed higher intensity in FoxO3tub cells. DHE (middle panel) showed that nearly 100% of FoxO3tub cells emitted red nuclear signals compared with 49.6% in FoxO3ctl cells. Right panel: DHE staining of the kidney showed stronger nuclear oxidative stress in FoxO3tub kidneys 4 weeks after IRI. (C) EM images show dramatic mitochondrial swelling with a loss of cristae in epithelial cells 4 weeks after IRI. In FoxO3tub cells, frequent ruptures of mitochondrial inner and outer membranes were detected (white arrow). Scale bars: 10 μm (left panel in B), 50 μm (middle panel in B), and 100 μm (right panel in B); 2 μm (left and middle panels in C) and 1 μm (right panel in C).