FoxO3 activation in hypoxic tubules prevents chronic kidney disease
Ling Li, … , Qais Al-Awqati, Fangming Lin
Ling Li, … , Qais Al-Awqati, Fangming Lin
Published June 3, 2019; First published March 26, 2019
Citation Information: J Clin Invest. 2019;129(6):2374-2389. https://doi.org/10.1172/JCI122256.
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Categories: Research Article Cell biology Nephrology

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 1

Severe renal IRI leads to CKD, hypoxia, and activation of autophagy and FoxO3.

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Severe renal IRI leads to CKD, hypoxia, and activation of autophagy and ...
(A) Mice were subjected to 45 minutes of unilateral left renal IRI, and the kidneys were examined up to 4 weeks after IRI. Representative PAS stainings indicate partial repair and CKD development after initial IRI. Arrows denote tubular atrophy, and arrowheads indicate cast formation in the lumens of tubules. (B) Reduction of the density of renal microvessels is identified by the endothelial marker endomucin (Endo, green) and renal hypoxia is indicated by the intensity of the hypoxia-dependent pimonidazole protein adducts (Pim, red). n = 4 for normal controls; n = 7 for 1, 2, and 4 weeks after IRI. (C) Increased renal autophagy with a higher LC3II/LC3I ratio during CKD development. n = 5. GAPDH served as a loading control. (D) Appearance of autophagic dots (RFP dots, arrows) in tubules surrounding a low density of capillaries labeled with endomucin (Endo, white). (E) FoxO3 activation with nuclear expression (red) in renal tubules labeled with E-cadherin (green, E-cdh). n = 4 for normal controls; n = 5 for IRI at 1, 2, and 4 weeks. Nuclei were counterstained with DAPI (blue) in D and E. Scale bars: 100 μm (A), 50 μm (B), and 20 μm (D and E). *P ˂ 0.05 compared with normal controls, by 1-way ANOVA followed by Dunnett’s post hoc test for multiple comparisons (B, C, and E).