Synergistic induction of monocyte chemoattractant protein-1 by integrins and platelet-derived growth factor via focal adhesion kinase in mesangial cells

• Published in: Nephrology, dialysis, transplantation Vol. 20; no. 10; pp. 2080 - 2088
• Main Authors: Kanegae, Kaori, Tamura, Masahito, Kabashima, Narutoshi, Serino, Ryota, Tokunaga, Masaki, Oikawa, Shigeru, Nakashima, Yasuhide
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2005; Oxford Publishing Limited (England)
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Base Sequence; Biological and medical sciences; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Cell Adhesion; Cells, Cultured; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; DNA - genetics; Drug Synergism; Emergency and intensive care: renal failure. Dialysis management; extracellular matrix; Fibronectins - administration & dosage; Fibronectins - metabolism; gene expression; Glomerular Mesangium - cytology; Glomerular Mesangium - drug effects; Glomerular Mesangium - metabolism; Glomerulonephritis; growth factor; integrin; Integrins - metabolism; Intensive care medicine; MAP Kinase Signaling System; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Platelet-Derived Growth Factor - administration & dosage; Platelet-Derived Growth Factor - metabolism; Proto-Oncogene Proteins c-sis; Rats; Signal Transduction; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Kidney disease; Glomerulonephritis; Urinary system disease; Monocyte; Mesangial cell; Hemodialysis; Gene expression; Extrarenal dialysis; Integrin; cell adhesion; Renal failure; Extracellular matrix; Platelet derived growth factor; Growth factor
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfh998

Background. Growth factors, extracellular matrix and its receptor integrins are upregulated in various glomerular diseases. We investigated the mechanism of collaboration between integrins and platelet-derived growth factor (PDGF) in focal adhesion kinase (FAK)- and extracellular signal-related kinase (ERK)1/2-mediated signal pathways that lead to monocyte chemoattractant protein (MCP)-1 expression in cultured rat mesangial cells (MCs). Methods. Serum-starved MCs were plated on fibronectin- or polylysine-coated plates with or without PDGF, and examined for phosphorylation of ERK1/2, mitogen-activated protein or ERK kinase (MEK)1/2 and FAK by western blotting, and for expression of MCP-1 mRNA and protein by reverse transcription–polymerase chain reaction (RT–PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The effects of dominant-negative FAK on MCP-1 expression were examined. Results. Cell adhesion to fibronectin increased phosphorylation of FAK, MEK1/2 and ERK1/2, and induced MCP-1 mRNA and protein expression. PDGF increased phosphorylation of FAK, MEK1/2 and ERK1/2 even without cell adhesion to fibronectin, and induced MCP-1 mRNA and protein expression. PDGF with integrin activation by fibronectin synergistically increased phosphorylation of FAK, MEK1/2 and ERK1/2, and expression of MCP-1 mRNA and protein. Dominant-negative FAK attenuated fibronectin enhancement of PDGF-induced ERK1/2 phosphorylation and MCP-1 expression, indicating involvement of FAK in this signalling. Conclusions. Our results suggest the cooperative role of integrin and PDGF receptor in activation of the ERK pathway possibly via FAK in MCs. The synergistic activation of integrin and PDGF signalling may play an important role in the progression of glomerular diseases through the induction of MCP-1.