title: Interactions between HIF-1α and AMPK in the regulation of cellular hypoxia adaptation in chronic kidney disease.
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.
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Satriano
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California; and.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California; and Center for Renal Translational Medicine, University of California, San Diego, California.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California; and Center for Renal Translational Medicine, University of California, San Diego, California.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Núria M
authors.initials: NM
authors.lastname: Pastor-Soler
authors.affiliation: Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California;
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hallows
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, University of California and Veterans Affairs San Diego Healthcare System, San Diego, California; and p1singh@ucsd.edu.
authors.forename: Prabhleen
authors.initials: P
authors.lastname: Singh
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000222:Adaptation, Physiological / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; hypoxia inducible factor-1α