Molecular regulation and function of FoxO3 in chronic kidney disease

We review the function and regulation of FOXO transcription factors, the mechanism of FOXO3 activation in the kidney, and the role of FOXO3 in delaying the development of chronic kidney disease

Fangming Lin


Scholarcy highlights

  • Our incomplete understanding of the pathobiology in the initiation and progression of chronic kidney disease limits the development of effective measures to prevent and treat CKD
  • Knocking-down studies suggest that all three prolyl hydroxylase domain isoforms that are known to be expressed in the kidney can catalyze prolyl hydroxylation of FoxO3
  • FoxO3 activation under hypoxic conditions is partially dependent on Hif1, as deletion of Hif-1α attenuated the increase of FoxO3 mRNA and protein, suggesting a molecular nexus in kidney stress response
  • Sensing environmental changes, such as growth factor deficiency and stress from nutrient scarcity, hypoxia and reactive oxygen species, multiple upstream pathways are activated and converge on FOXO3, which activates a plethora of stress responsive genes to adapt the changing environment
  • We show that in human kidneys biopsied for AKI or AKI-on-CKD, vascular dropout, and increased nuclear FOXO3 expression coexist with autophagosomes and autolysosomes in injured proximal tubules
  • FOXO3 is activated in response to metabolic and oxidative stress to reduce tubular injury and promote cell survival
  • A more in-depth understanding of the pathogenesis of chronic kidney disease and FOXO signaling and function during the difference phase of kidney injury, and effective or futile repair is prerequisite before harnessing FOXO for preventing and treating kidney disease

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