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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Collagen I upregulates extracellular matrix gene expression and secretion of TGF-1 by cultured human mesangial cells

¹Departments of Physiology and ²Medicine, Alcala University, ³Nephrology Section and Research Unit, Hospital Principe de Asturias, and Instituto Reina Sofía de Investigaciones Nefrológicas, 28800 Madrid, Spain

Submitted 3 July 2003 ; accepted in final form 3 February 2004

Progressive renal diseases are characterized by an increased synthesis of extracellular matrix (ECM) components. The mechanisms involved in the development of these alterations are not completely known, but a crucial role for TGF-1 has been suggested. Moreover, the ability of the ECM to modulate the phenotypic expression of different cell types has been widely described. In experiments presented here, human mesangial cells (HMC) were grown on collagen type I (COL I) or IV (COL IV). ECM protein and TGF-1 mRNA expression were evaluated by Northern blot analysis, and TGF-1 secretion was evaluated by ELISA. The involvement of tyrosine kinase and serine-threonine kinase pathways was studied by Western blot analysis, immunofluorescence, and in vitro kinase assays. HMC cultured on COL I showed an increased mRNA expression of COL I and COL IV, fibronectin, and TGF-1. Both tyrosine phosphorylation and integrin-linked kinase (ILK) activity increased when HMC were cultured on COL I, and blockade of these pathways inhibited the increased secretion of TGF-1. In conclusion, the present results support a role for extracellular COL I in the regulation of TGF-1 synthesis during progressive renal sclerosis and fibrosis and the subsequent increase in newly synthesized ECM proteins. In addition, ILK, along with the tyrosine kinases, participates in the genesis of this effect.

fibrosis; tyrosine phosphorylation; integrin-linked kinase

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