Shear stress induces cell apoptosis via a c-Src-phospholipase D-mTOR signaling pathway in cultured podocytes

详细信息	查看全文 | 推荐本文 |

• 作者：Chunfa Huang^a ; ^b ; ^c ; ^{chunfa.huang@case.edu} ; Leslie A. Bruggeman^b ; ^c ; Lindsey M. Hydo^a ; R. Tyler Miller^a ; ^b ; ^c
• 关键词：PA ; phosphatidic acid ; PC ; phosphatidylcholine ; PEt ; phosphatidylethanol ; PLD ; phospholipase D ; mTOR ; mammalian target of rapamycin ; S6K ; p70S6 kinase
• 刊名：Experimental Cell Research
• 出版年：2012
• 期刊代码：292_00144827
• 类别：med
• 出版时间：10 June, 2012
• 卷：318
• 期：10
• 页码：1075-1085
• 文件大小：1996 K

摘要

The glomerular capillary wall, composed of endothelial cells, the glomerular basement membrane and the podocytes, is continually subjected to hemodynamic force arising from tractional stress due to blood pressure and shear stress due to blood flow. Exposure of glomeruli to abnormal hemodynamic force such as hyperfiltration is associated with glomerular injury and progressive renal disease, and the conversion of mechanical stimuli to chemical signals in the regulation of the process is poorly understood in podocytes. By examining DNA fragmentation, apoptotic nuclear changes and cytochrome c release, we found that shear stress induced cell apoptosis in cultured podocytes. Meanwhile, podocytes exposed to shear stress also stimulated c-Src phosphorylation, phospholipase D (PLD) activation and mammalian target of rapamycin (mTOR) signaling. Using the antibodies against c-Src, PLD₁, and PLD₂ to perform reciprocal co-immunoprecipitations and in vitro PLD activity assay, our data indicated that c-Src interacted with and activated PLD₁ but not PLD₂. The inhibition of shear stress-induced c-Src phosphorylation by PP₂ (a specific inhibitor of c-Src kinase) resulted in reduced PLD activity. Phosphatidic acid, produced by shear stress-induced PLD activation, stimulated mTOR signaling, and caused podocyte hypertrophy and apoptosis.