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Activation of AMP-Activated Protein Kinase Inhibits Albumin-Induced Endoplasmic Reticulum Stress and Apoptosis through Inhibition of Reactive Oxygen Species.

Nephron Exp Nephrol. 2012 Oct 25;121(1):e38-e48

Authors: Lee EK, Jeong JU, Chang JW, Yang WS, Kim SB, Park SK, Park JS, Lee SK


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. Method: 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. Conclusion: 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.

PMID: 23108012 [PubMed - as supplied by publisher]