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.
Highlights
Renal tubulointerstitial fibrosis which is characterized by aberrant activation and renal fibroblasts growths is a common pathway in end-stage renal disease [1,2]
Pre-incubation with the AMPKspecific inhibitor compound C dose-dependently blocked the inhibitory effects of aminoimidazole-4-carboxyamide ribonucleoside (AICAR) on a-smooth muscle actin (a-smooth muscle actin (SMA)) expression in NRK-49F cells stimulated with Transforming growth factor-b1 (TGF-b1) (Fig. 6B). These results revealed that the inhibitory effect of AICAR on TGF-b1-induced fibroblastmyofibrobalst transformation is partially mediated through the activation of AMPKa1
Activation of myofibroblasts by TGF-b1 leads to extracellular matrix (ECM) production, followed by progressive fibrosis and tubular atrophy [36]
Summary
Renal tubulointerstitial fibrosis which is characterized by aberrant activation and renal fibroblasts growths is a common pathway in end-stage renal disease [1,2]. Differentiation of renal interstitial fibroblasts into a-SMA (+) myofibroblasts is the crucial step in the development of renal fibrosis. Targeting the signaling pathways that mediate fibroblast-myofibroblast transformation may attenuate the progression of renal fibrosis. Transforming growth factor-b1 (TGF-b1) signaling is the most important pathway associated with renal fibroblast-myofibroblast activation [4,5,6]. In addition to the canonical TGF-b/Smads pathway, TGF-b1 induces myofibroblast activation and renal fibrosis through non-Smad signaling pathways, including mitogenactivated protein kinase (MAPK), PI3K-Akt, small GTPase pathways, and etc. In addition to the canonical TGF-b/Smads pathway, TGF-b1 induces myofibroblast activation and renal fibrosis through non-Smad signaling pathways, including mitogenactivated protein kinase (MAPK), PI3K-Akt, small GTPase pathways, and etc. [9,10]
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