title: FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F-actin re-organization via activating p38 in response to ox-LDL.
abstract: 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.
authors.affiliation: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Mengsi
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Obstetrics and Gynecology, The Second Hospital of Shandong University, Jinan, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Pathology, School of Medicine, Shandong University, Jinan, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhen
authors.affiliation: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Jiangong
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000378:metabolism*; D008077:Lipoproteins, LDL; D008297:Male; D010766:Phosphorylation / Q000502:physiology; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D051417:Focal Adhesion Kinase 1; C496052:Ptk2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases
keywords: 
  FAK
  ; cytoskeleton; hypercholesterolaemia; ox-LDL; p38; podocyte