title: The AMPK agonist AICAR inhibits TGF-β1 induced activation of kidney myofibroblasts.
abstract: Activation of interstitial myofibroblasts and excessive production of extracellular matrix proteins are common pathways that contribute to chronic kidney disease. In a number of tissues, AMP-activated kinase (AMPK) activation has been shown to inhibit fibrosis. Here, we examined the inhibitory effect of the AMPK activator, 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), on renal fibrosis in vivo and TGF-β1-induced renal fibroblasts activation in vitro. A unilateral ureteral obstruction (UUO) model was induced in male BALB/c mice. Mice with UUO were administered AICAR (500 mg/Kg/day) or saline intraperitoneally 1 day before UUO surgery and daily thereafter. Both kidneys were harvested 7 days after surgery for further analysis. For the in vitro studies, NRK-49F rat fibroblasts were pre-incubated with AICAR before TGF-β1 stimulation. The inhibitory effects of AICAR on signaling pathways down-stream of TGF-β1 were analyzed. In UUO model mice, administration of AICAR attenuated extracellular matrix protein deposition and the expression of α-smooth muscle actin (α-SMA), type I collagen and fibronectin. Pre-incubation of NRK-49F cells with AICAR inhibited TGF-β1-induced myofibroblast activation. Silencing of AMPKα1 by siRNA or by blocking AMPK activation with Compound C diminished the inhibitory effect of AICAR. Moreover, the inhibitory effects of AICAR on TGF-β1-mediated myofibroblast activation were associated with down-regulation of ERK 1/2 and STAT3. Our results suggest that AICAR reduces tubulointerstitial fibrosis in UUO mice and inhibits TGF-β1-induced kidney myofibroblast activation. AMPK activation by AICAR may have therapeutic potential for the treatment of renal tubulointerstitial fibrosis.
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Kuan-Hsing
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Hsiang-Hao
authors.initials: HH
authors.lastname: Hsu
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Tzu-Hai
authors.initials: TH
authors.lastname: Yen
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Ko
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Yang
authors.affiliation: Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Hung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D058628:Myofibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D012265:Ribonucleotides / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D053773:Transforming Growth Factor beta1; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide