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- 2018
PPAR-γ通过活化PTEN抑制肾间质成纤维细胞MMP2的活化
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Abstract:
摘要：目的 探讨激活的PPAR-γ是否通过活化PTEN抑制血小板源性生长因子(PDGF)刺激的肾间质成纤维细胞MMP2活化，从而介导肾间质纤维化的发生。方法 以原代分离培养的小鼠肾间质成纤维细胞为研究对象，以肾间质纤维化的主要刺激因子PDGF-AA刺激细胞。于PDGF-AA刺激细胞前，分别予以罗格列酮激活PPAR-γ，PI3K、PTEN、PPAR-γ特异性抑制剂LY294002、bpV(Pic)、GW9662预处理细胞，检测AKT、PTEN、PPAR-γ、MMP2的活化水平。结果 成功分离并培养小鼠肾间质成纤维细胞，并证实PDGF-AA可剂量依赖性激活MMP2，而对MMP9、TIMPs无影响。特异性抑制PI3K/AKT信号通路或激活PPAR-γ显著抑制PDGF-AA刺激的AKT、MMP2活性；抑制PTEN可逆转PPAR-γ激活对PDGF-AA诱导的AKT磷酸化及MMP2活性的影响。结论 PI3K/AKT信号通路特异性介导PDGF-AA诱导的肾间质成纤维细胞MMP2的活化；激活的PPAR-γ通过活化PTEN抑制PI3K/AKT信号通路进而抑制MMP2活化。
ABSTRACT: Objective To investigate the hypothesis that activation of PPAR-γ regulates renal remodeling by modulating matrix metalloproteinase 2 (MMP2) activation in primary cultured renal interstitial fibroblasts. Methods In our present study, platelet-derived growth factor-AA (PDGF-AA), a key stimulator of RIF, was applied to stimulate primary cultured mouse renal interstitial fibroblasts. The selective inhibitor of PI3K or PTEN was used to investigate the involvement of the above molecular mediators in PDGF-induced MMP2 production. Results PDGF-AA dose-dependently induced MMP2 activation in primary cultured mouse renal interstitial fibroblasts. This effect was blocked by inhibition of PI3K/AKT signal pathway. PDGF-AA did not significantly affect the generation of tissue inhibitors of matrix metalloproteinases (TIMPs). Pre-incubation of cells with rosiglitazone blocked PDGF-stimulated MMP2 activation, and this effect was particularly coupled to PPAR-γ activation of PTEN and inhibition of AKT phosphorylation. Inhibition of PTEN by bpV(Pic) restored the suppression of PPAR-γ on phosphorylation of AKT and subsequent MMP2 production. Conclusion Our results indicate that activation of PI3K/AKT signaling mediated PDGF-induced MMP2 activation. PPAR-γ inhibited MMP2 secretion by activating PTEN and subsequent suppression of AKT phosphorylation
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