The AMPK agonist AICAR inhibits TGF-β1 induced activation of kidney myofibroblasts

• Published in: PloS one 2014-09, Vol.9 (9), p.e106554-e106554
• Main Authors: Chen, Kuan-Hsing, Hsu, Hsiang-Hao, Lee, Cheng-Chia, Yen, Tzu-Hai, Ko, Yi-Ching, Yang, Chih-Wei, Hung, Cheng-Chieh
• Format: Article
• Language: English
• Subjects: Actin; Activation; Adenosine; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animal tissues; Animals; Apoptosis; Biology and Life Sciences; Blotting, Western; Cell cycle; Collagen (type I); Collagen Type I - metabolism; Cytokines; Extracellular matrix; Extracellular signal-regulated kinase; Fibroblasts; Fibronectin; Fibronectins - metabolism; Fibrosis; Fluorescent Antibody Technique; Gene expression; Glucose; Growth factors; Immunoglobulins; Immunohistochemistry; Incubation; Kidney - cytology; Kidney diseases; Kidneys; Kinases; Male; Matrix protein; Medicine; Medicine and Health Sciences; Metabolism; Mice; Mice, Inbred BALB C; Muscles; Myofibroblasts - cytology; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Phosphorylation; Proteins; Real-Time Polymerase Chain Reaction; Ribonucleotides - pharmacology; RNA, Small Interfering; Rodents; Signaling; siRNA; Smooth muscle; Stat3 protein; Surgery; Transforming Growth Factor beta1 - pharmacology; Transforming growth factor-b1
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0106554

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.