title: Activation of AMP-activated protein kinase inhibits albumin-induced endoplasmic reticulum stress and apoptosis through inhibition of reactive oxygen species.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress induced by urinary albumin plays an important role in tubulointerstitial injury. We have shown that albumin-induced ER stress is regulated through reactive oxygen species (ROS)-c-Src kinase-mTOR signaling pathways. We postulated that peroxisome proliferator-activated receptor-γ (PPAR-γ) might also act as an upstream signaling molecule between c-Src kinase and mTOR. It has been suggested that AMP-activated protein kinase (AMPK) is involved in attenuation of ER stress. We examined whether and how activation of AMPK suppressed the albumin-induced ER stress and apoptosis in tubular epithelial cells.
  
  
  METHODS
  HK-2 cells, a proximal tubular cell line, were used. Protein expressions were measured by Western blot analysis. Intracellular ROS and apoptosis were analyzed by flow cytometry.
  
  
  RESULTS
  Albumin-induced PPAR-γ expression and PPAR-γ inhibitor (GW9662) suppressed the albumin-induced ER stress. c-Src kinase inhibitor and GW9662 reduced the albumin-induced PPAR-γ and mTOR, respectively. Metformin (the best known clinical activator of AMPK) and another AMPK activator (AICAR) suppressed the albumin-induced ER stress via inhibition of ROS through induction of endogenous antioxidant thioredoxin. AMPK inhibitor blocked the effect of metformin and AICAR. Our in vivo animal study showed that metformin reduced the renal cortical expression of ER stress protein (GRP78) in protein-overload proteinuria rats. Metformin also reduced the caspase 3-dependent apoptosis induced by albumin.
  
  
  CONCLUSIONS
  PPAR-γ was involved in albumin-induced ER stress as an upstream signaling molecule between c-Src kinase and mTOR. AMPK activation might be beneficial in attenuating the tubulointerstitial injury induced by albumin.
authors.affiliation: Department of Internal Medicine, Dankook University Hospital, Cheonan, Republic of Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Lee
authors.forename: Jin Uk
authors.initials: JU
authors.lastname: Jeong
authors.forename: Jai Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Won Seok
authors.initials: WS
authors.lastname: Yang
authors.forename: Soon Bae
authors.initials: SB
authors.lastname: Kim
authors.forename: Su Kil
authors.initials: SK
authors.lastname: Park
authors.forename: Jung Sik
authors.initials: JS
authors.lastname: Park
authors.forename: Sang Koo
authors.initials: SK
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012709:Serum Albumin / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; D012709:Serum Albumin; D055372:AMP-Activated Protein Kinases