PPAR-γ通过活化PTEN抑制肾间质成纤维细胞MMP2的活化  

PPAR-γinhibits PDGF-induced MMP2 generation by activating PTEN in mouse renal interstitial fibroblasts

作　　者：卢家美[1] 刘丹[1] 张苏梅[2] 杨艳艳[1] 吕治安[1] 韩锦[1] 付荣国[1] LU Jia-mei;LIU Dan;ZHANG Su-mei;YANG Yan-yan;Lv Zhi-an;HAN Jin;FU Rong-guo(Department of Nephrology,the Second Affiliated Hospital of Xi’an Jiaotong University,Xi’an 710004;Department of Nursing,Xi’an Medical College,Xi’an 710021,China)

机构地区：[1]西安交通大学第二附属医院肾病内科,陕西西安710004 [2]西安医学院护理学院,陕西西安710021

出　　处：《西安交通大学学报（医学版）》2018年第3期386-391,共6页Journal of Xi’an Jiaotong University（Medical Sciences）

基　　金：国家自然科学基金资助项目(No.81700605)~~

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。Objective To investigate the hypothesis that activation of PPAR-γregulates 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-γactivation of PTEN and inhibition of AKT phosphorylation.Inhibition of PTEN by bpV(Pic)restored the suppression of PPAR-γon phosphorylation of AKT and subsequent MMP2 production.Conclusion Our results indicate that activation of PI3K/AKT signaling mediated PDGF-induced MMP2 activation.PPAR-γinhibited MMP2 secretion by activating PTEN and subsequent suppression of AKT phosphorylation.

关 键 词：肾间质纤维化 肾间质成纤维细胞 血小板源性生长因子 基质金属蛋白酶-2 过氧化物酶体增殖物激活受体-Γ 

分 类 号：R692[医药卫生—泌尿科学]