期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 21, 期 3, 页码 552-567出版社
WILEY
DOI: 10.1111/jcmm.13001
关键词
podocyte; hypercholesterolaemia; ox-LDL; FAK; p38; cytoskeleton
资金
- National Natural Science Foundation of China [30971381, 81370834, 81400732]
- Shandong Young Scientists Award Fund [2010BSB14076]
- Chinese Society of Nephrology Scientific Fund [14050480585]
Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet-induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder-related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c-Src, Rho GTPase and mitogen-activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low-density lipoprotein (ox-LDL) triggered hyper-phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re-arrangement of F-actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre-treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper-activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox-LDL damaged podocytes in a FAK/p38-dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia-related podocyte damage and proteinuria.
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