TGF-β1 Protects against Mesangial Cell Apoptosis via Induction of Autophagy
TGF-β1 Protects against Mesangial Cell Apoptosis via Induction of Autophagy
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DOI：
10.1074/jbc.m109.093724
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发表时间：
2010-11-26
影响因子：
4.8
通讯作者：
Choi, Mary E.
中科院分区：
文献类型：
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作者：
Ding, Yan;Kim, Jin Kuk;Choi, Mary E.
自噬可以导致细胞在应激反应中死亡，但它也可以作为细胞存活的保护机制。我们发现，TGF-β 1诱导自噬和保护肾小球系膜细胞在血清剥夺过程中发生凋亡。通过增加微管相关蛋白1轻链3（LC 3）水平和自噬囊泡相关形式LC 3-II的点状分布，血清戒断在1小时内迅速诱导小鼠肾小球系膜细胞（MMC）的自噬。我们证明，1小时后，有一个时间依赖性的降低LC 3水平，伴随着诱导细胞凋亡，证明增加裂解caspase 3。然而，用TGF-β 1处理导致诱导自噬蛋白LC 3，同时抑制半胱天冬酶3活化。TGF-β 1不能拯救MMC免于通过siRNA敲低LC 3后的血清剥夺诱导的细胞凋亡，并且不能拯救来自LC 3缺失（LC 3（-/-））小鼠的MMC。我们发现TGF-β 1通过TAK 1和Akt激活诱导自噬，LY 294002或显性负性Akt抑制PI 3 K-Akt通路抑制LC 3水平并增强caspase 3激活。TGF-β 1还上调细胞周期蛋白D1和E蛋白水平，同时下调p27，从而刺激细胞周期进程。巴弗洛霉素A1，而不是MG 132，阻断TGF-β 1下调p27，表明p27水平通过自噬调节。综上所述，我们的数据表明，TGF-β 1通过激活Akt通路诱导自噬，从血清剥夺诱导的细胞凋亡中拯救MMC。自噬过程可能通过抑制细胞凋亡和促进系膜细胞存活，构成肾小球损伤的适应机制。
Autophagy can lead to cell death in response to stress, but it can also act as a protective mechanism for cell survival. We show that TGF-beta 1 induces autophagy and protects glomerular mesangial cells from undergoing apoptosis during serum deprivation. Serum withdrawal rapidly induced autophagy within 1 h in mouse mesangial cells (MMC) as determined by increased microtubule-associated protein 1 light chain 3 (LC3) levels and punctate distribution of the autophagic vesicle-associated-form LC3-II. We demonstrate that after 1 h there was a time-dependent decrease in LC3 levels that was accompanied by induction of apoptosis, evidenced by increases in cleaved caspase 3. However, treatment with TGF-beta 1 resulted in induction of the autophagy protein LC3 while suppressing caspase 3 activation. TGF-beta 1 failed to rescue MMC from serum deprivation-induced apoptosis upon knockdown of LC3 by siRNA and in MMC from LC3 null (LC3(-/-)) mice. We show that TGF-beta 1 induced autophagy through TAK1 and Akt activation, and inhibition of PI3K-Akt pathway by LY294002 or dominant-negative Akt suppressed LC3 levels and enhanced caspase 3 activation. TGF-beta 1 also up-regulated cyclin D1 and E protein levels while down-regulating p27, thus stimulating cell cycle progression. Bafilomycin A1, but not MG132, blocked TGF-beta 1 down-regulation of p27, suggesting that p27 levels were regulated through autophagy. Taken together, our data indicate that TGF-beta 1 rescues MMC from serum deprivation-induced apoptosis via induction of autophagy through activation of the Akt pathway. The autophagic process may constitute an adaptive mechanism to glomerular injury by inhibiting apoptosis and promoting mesangial cell survival.