Abstract
Progression of chronic kidney disease (CKD) is characterized by the accumulation of extracellular matrix. Especially, α -SMA positive myofibroblasts, which produce high amounts of TGF- β 1, plays a key role in interstitial fibrosis. Previous studies demonstrated hepatocyte growth factor (HGF) improved kidney fibrosis, whereas mechanisms of HGF on prevention of renal fibrosis have not been fully understood. Since HGF may contribute to myofibroblasts apoptosis/anoikis, we tested whether HGF increased MMP expressions and contributed to myofibroblasts apoptosis/anoikis. When human mesangial cells were treated with TGF- β 1, cells phenotypically changed to myofibroblasts, and this was associated with up-regulation of c-Met/HGF receptor (P<0.05). HGF significantly increased MMP-2/-9 expression (P<0.05) of myofibroblasts. Furthermore, HGF increased phosphorylation of Tyr925 FAK, suggesting the role of MMPs and FAK on HGF induced apoptosis. Indeed, when GM6001(GM;MMP inhibitor) or FAK siRNA were treated in combination with HGF, HGF-mediated myofibroblast apoptosis was significantly inhibited (HGF alone; 8.1±0.2%, HGF+GM; 3.4±0.2%, HGF+FAK siRNA; 3.6±0.3%, P<0.05). Next, we tested the anti-fibrotic effect of HGF using cardiac specific HGF over-expressing mice (HGF-Tg). Angiotensin II (Ang II) infusion induced renal fibrosis in litter mates control, while it was significantly inhibited in HGF-Tg accompanied with the significant depletion of interstitial myofibroblasts (P<0.05). TGF β -1, collagen type I and IV mRNA in HGF-Tg were significantly reduced compared to control (qPCR; P<0.05). Consistent with the in vitro studies, HGF-Tg significantly increased MMP-2/-9 expression (P<0.05). TUNEL and α -SMA double-positive cells induced by Ang II, which represents myofibroblasts apoptosis, was reduced in HGF-Tg compared to control (3.7±0.3 vs 1.7±0.4%, P<0.05). Furthermore, GM6001 injections in HGF-Tg with Ang II cancelled the anti-fibrotic effects of HGF accompanied with the depletion of myofibroblasts. In summary, increased activities of FAK-MMPs underlie the major mechanism of HGF mediated anoikis/apoptosis of myofibroblasts. Activation of MMPs by HGF might be a target to attenuate the progression of renal fibrosis in CKD.
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