FoxO3 activation in hypoxic tubules prevents chronic kidney disease

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2374-2389
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number6
DOIs
StatePublished - Jun 3 2019
Externally publishedYes

Fingerprint

Chronic Renal Insufficiency
Kidney
Acute Kidney Injury
Wounds and Injuries
Transcription Factors
Prolyl Hydroxylases
Hydroxylation
Fibrosis
Hypoxia
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

FoxO3 activation in hypoxic tubules prevents chronic kidney disease. / Li, Ling; Kang, Huimin; Zhang, Qing; D’Agati, Vivette D.; Al-Awqati, Qais; Lin, Fangming.

In: Journal of Clinical Investigation, Vol. 129, No. 6, 03.06.2019, p. 2374-2389.

Research output: Contribution to journalArticle

Li, L, Kang, H, Zhang, Q, D’Agati, VD, Al-Awqati, Q & Lin, F 2019, 'FoxO3 activation in hypoxic tubules prevents chronic kidney disease', Journal of Clinical Investigation, vol. 129, no. 6, pp. 2374-2389. https://doi.org/10.1172/JCI122256
Li, Ling ; Kang, Huimin ; Zhang, Qing ; D’Agati, Vivette D. ; Al-Awqati, Qais ; Lin, Fangming. / FoxO3 activation in hypoxic tubules prevents chronic kidney disease. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 6. pp. 2374-2389.
@article{5515543693824fd982d14a716dc9fa6d,
title = "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.",
author = "Ling Li and Huimin Kang and Qing Zhang and D’Agati, {Vivette D.} and Qais Al-Awqati and Fangming Lin",
year = "2019",
month = "6",
day = "3",
doi = "10.1172/JCI122256",
language = "English (US)",
volume = "129",
pages = "2374--2389",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

TY - JOUR

T1 - FoxO3 activation in hypoxic tubules prevents chronic kidney disease

AU - Li, Ling

AU - Kang, Huimin

AU - Zhang, Qing

AU - D’Agati, Vivette D.

AU - Al-Awqati, Qais

AU - Lin, Fangming

PY - 2019/6/3

Y1 - 2019/6/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85063711890&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063711890&partnerID=8YFLogxK

U2 - 10.1172/JCI122256

DO - 10.1172/JCI122256

M3 - Article

C2 - 30912765

AN - SCOPUS:85063711890

VL - 129

SP - 2374

EP - 2389

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 6

ER -