title: Activation of AMP-activated protein kinase inhibits ER stress and renal fibrosis.
abstract: It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal fibrosis. We examined whether and how activation of AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [tunicamycin (TM) and thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal fibrosis. Western blot analysis, immunofluorescence, small interfering (si)RNA experiments, and immunohistochemical staining were performed. Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of glucose-related protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of heme oxygenase-1. Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as metformin. Transfection with siRNA targeting AMPK blocked the effect of metformin. Consistent with the results of cell culture experiments, metformin reduced renal cortical GRP78 expression and increased heme oxygenase-1 expression in a mouse model of ER stress-induced acute kidney injury by TM. Activation of AMPK also suppressed ER stress by transforming growth factor-β, ANG II, aldosterone, and high glucose. Furthermore, metformin reduced GRP78 expression and renal fibrosis in a mouse model of unilateral ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal fibrosis.
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Hyosang
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Moon
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Joon-Seok
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Chung Hee
authors.initials: CH
authors.lastname: Baek
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Miyeon
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Min
authors.affiliation: Department of Internal Medicine, Asan Medical Center, Asan Institute for Life Sciences, University of Ulsan, Seoul, Korea sklee2@amc.seoul.kr.
authors.forename: Sang Koo
authors.initials: SK
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004789:Enzyme Activation; D005355:Fibrosis / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D014415:Tunicamycin; D008687:Metformin; D051547:Heme Oxygenase-1; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; endoplasmic reticulum stress; fibrosis; heme oxygenase-1; metformin