Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease

Hui Li, Joseph Satriano, Joanna L. Thomas, Satoshi Miyamoto, Kumar Sharma, Núria M. Pastor-Soler, Kenneth R. Hallows, Prabhleen Singh

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Renal hypoxia contributes to chronic kidney disease (CKD) progression, as validated in experimental and human CKD. In the early stages, increased oxygen consumption causes oxygen demand/supply mismatch, leading to hypoxia. Hence, early targeting of the determinants and regulators of oxygen consumption in CKD may alter the disease course before permanent damage ensues. Here, we focus on hypoxia inducible factor-1α (HIF-1α) and AMP-activated protein kinase (AMPK) and on the mechanisms by which they may facilitate cellular hypoxia adaptation. We found that HIF-1α activation in the subtotal nephrectomy (STN) model of CKD limits protein synthesis, inhibits apoptosis, and activates autophagy, presumably for improved cell survival. AMPK activation was diminished in the STN kidney and was remarkably restored by HIF-1α activation, demonstrating a novel role for HIF-1α in the regulation of AMPK activity. We also investigated the independent and combined effects of HIF-1α and AMPK on cell survival and death pathways by utilizing pharmacological and knockdown approaches in cell culture models. We found that the effect of HIF-1α activation on autophagy is independent of AMPK, but on apoptosis it is partially AMPK dependent. The effects of HIF-1α and AMPK activation on inhibiting protein synthesis via the mTOR pathway appear to be additive. These various effects were also observed under hypoxic conditions. In conclusion, HIF-1α and AMPK appear to be linked at a molecular level and may act as components of a concerted cellular response to hypoxic stress in the pathophysiology of CKD.

Original languageEnglish
Pages (from-to)F414-F428
JournalAmerican Journal of Physiology - Renal Physiology
Volume309
Issue number5
DOIs
Publication statusPublished - Sep 4 2015
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
Cell Hypoxia
AMP-Activated Protein Kinases
Chronic Renal Insufficiency
Autophagy
Nephrectomy
Oxygen Consumption
Cell Survival
Apoptosis
Kidney
Disease Progression
Proteins
Cell Death
Cell Culture Techniques
Pharmacology
Oxygen

Keywords

  • AMP-activated protein kinase
  • Hypoxia inducible factor-1α

ASJC Scopus subject areas

  • Physiology
  • Urology
  • Medicine(all)

Cite this

Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease. / Li, Hui; Satriano, Joseph; Thomas, Joanna L.; Miyamoto, Satoshi; Sharma, Kumar; Pastor-Soler, Núria M.; Hallows, Kenneth R.; Singh, Prabhleen.

In: American Journal of Physiology - Renal Physiology, Vol. 309, No. 5, 04.09.2015, p. F414-F428.

Research output: Contribution to journalArticle

Li, Hui ; Satriano, Joseph ; Thomas, Joanna L. ; Miyamoto, Satoshi ; Sharma, Kumar ; Pastor-Soler, Núria M. ; Hallows, Kenneth R. ; Singh, Prabhleen. / Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease. In: American Journal of Physiology - Renal Physiology. 2015 ; Vol. 309, No. 5. pp. F414-F428.
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