Synergistic effects of c-Jun and SP1 in the promotion of TGFβ1-mediated diabetic nephropathy progression

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• 作者：Pan Gao^a ; ^b ; Yingze Wei^a ; Zhigang Zhang^a ; Wenjiao Zeng^a ; Daming Sun^c ; Danyang Liu^a ; Bo Hou^a ; Congying Zhang^a ; Nong Zhang^a ; Hui Li^a ; ^{huili78@fudan.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Liliang Li^d ; ^{11111010016@fudan.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DM ; diabetes mellitus ; DN ; diabetic nephropathy ; ESRD ; end-stage renal disease ; ECM ; extracellular matrix ; TGFβ1 ; transforming growth factor-β1 ; HRMCs ; human renal mesangial cells ; ROS ; reactive oxygen species ; α-SMA ; α-smooth muscle actin ; Nrf2 ; nuclear factor erythroid 2-related factor 2 ; SFN ; sulforaphane ; FN ; fibronectin ; AP-1 ; activating protein-1 ; SP1 ; specificity protein 1 ; PAI-1 ; plasminogen activatorinhibitor-1 ; IHC ; immunohistochemistry ; Scr ; serum creatinine ; BUN ; blood urea nitrogen
• 刊名：Experimental and Molecular Pathology
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：100
• 期：3
• 页码：441-450
• 全文大小：2079 K

文摘

Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Transforming growth factor beta 1 (TGFβ1) is a well-distinguished mediator of progressive renal fibrosis in DN. However, the molecular mechanisms contributing to enhanced TGFβ1 expression in the progression of DN are not fully understood. Herein, we reported that c-Jun and specificity protein 1 (SP1) were critical upstream regulators of TGFβ1 expression in DN. The increase in c-Jun and SP1 expressions was positively correlated with TGFβ1 in both high glucose-treated human renal mesangial cells (HRMCs) and diabetic kidneys. Furthermore, c-Jun dose-dependently promoted SP1-mediated TGFβ1 transcription and vice versa. The synergistic effects of c-Jun and SP1 were attributed to their auto-regulation and cross-activation. Moreover, enhanced phosphorylation levels of c-Jun and SP1 were accompanied with increased TGFβ1 expression in diabetic kidneys. Accordingly, dephosphorylation of c-Jun and SP1 by the specific c-Jun N-terminal kinase (JNK) inhibitor SP600125 prevented the increase in TGFβ1 expression. These results suggested that c-Jun and SP1 synergistically activated profibrotic TGFβ1 expression in the development of DN by auto-regulation, cross-activation and phospho-modification.