+ Site Statistics
References:
52,654,530
Abstracts:
29,560,856
PMIDs:
28,072,755
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F-actin re-organization via activating p38 in response to ox-LDL



FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F-actin re-organization via activating p38 in response to ox-LDL



Journal of Cellular and Molecular Medicine 21(3): 552-567



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.

(PDF emailed within 0-6 h: $19.90)

Accession: 057851973

Download citation: RISBibTeXText

PMID: 27704688

DOI: 10.1111/jcmm.13001


Related references

Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte. Journal of Hypertension 28(5): 1034-1043, 2010

Intrinsic proinflammatory signaling in podocytes contributes to podocyte damage and prolonged proteinuria. American Journal of Physiology. Renal Physiology 303(10): F1473-F1485, 2013

KLF4-dependent epigenetic remodeling modulates podocyte phenotypes and attenuates proteinuria. Journal of Clinical Investigation 124(6): 2523-2537, 2014

Myo1e impairment results in actin reorganization, podocyte dysfunction, and proteinuria in zebrafish and cultured podocytes. Plos One 8(8): E72750, 2015

In vivo 17β-estradiol treatment contributes to podocyte actin stabilization in female db/db mice. Endocrinology 153(12): 5888-5895, 2013

The role of synaptopodin in the organization of the podocyte actin cytoskeleton. Journal of the American Society of Nephrology 13(Program and Abstracts Issue): 526A, September, 2002

Dynamic (re)organization of the podocyte actin cytoskeleton in the nephrotic syndrome. Pediatric Nephrology 19(2): 130-137, 2003

Amiloride reduces proteinuria and inhibits podocyte uPAR in the 5/6 nephrectomy rats. Nan Fang Yi Ke Da Xue Xue Bao 34(11): 1654-1657, 2015

Connective tissue growth factor modulates podocyte actin cytoskeleton and extracellular matrix synthesis and is induced in podocytes upon injury. Histochemistry and Cell Biology 136(3): 301-319, 2012

Non-muscle myosin-IIA is critical for podocyte f-actin organization, contractility, and attenuation of cell motility. Cytoskeleton 73(8): 377-395, 2017

Vasopeptidase inhibition attenuates proteinuria and podocyte injury in Zucker diabetic fatty rats. Naunyn-Schmiedeberg's Archives of Pharmacology 375(2): 95-103, 2007

Basic FGF accelerates podocyte injury, proteinuria, and glomerulosclerosis in experimental membranous nephropathy but not in normal rats. Kidney International 47(2): 677, 1995

GCS1, an Arf guanosine triphosphatase-activating protein in Saccharomyces cerevisiae, is required for normal actin cytoskeletal organization in vivo and stimulates actin polymerization in vitro. Molecular Biology of the Cell 10(3): 581-596, 1999

Proteinuria and fusion of podocyte foot processes in rats after infusion of cytokine from patients with idiopathic minimal lesion nephrotic syndrome. Nephron. Experimental Nephrology 102(3-4): E105-E112, 2005

Rac1 contributes to actin organization in glomerular podocytes. Nephron. Experimental Nephrology 114(3): E93-E106, 2010