title: Changes in extracellular matrix composition regulate cyclooxygenase-2 expression in human mesangial cells.
abstract: Glomerular diseases are characterized by a sustained synthesis and accumulation of abnormal extracellular matrix proteins, such as collagen type I. The extracellular matrix transmits information to cells through interactions with membrane components, which directly activate many intracellular signaling events. Moreover, accumulating evidence suggests that eicosanoids derived from cyclooxygenase (COX)-2 participate in a number of pathological processes in immune-mediated renal diseases, and it is known that protein kinase B (AKT) may act through different transcription factors in the regulation of the COX-2 promoter. The present results show that progressive accumulation of collagen I in the extracellular medium induces a significant increase of COX-2 expression in human mesangial cells, resulting in an enhancement in PGE(2) production. COX-2 overexpression is due to increased COX-2 mRNA levels. The study of the mechanism implicated in COX-2 upregulation by collagen I showed focal adhesion kinase (FAK) activation. Furthermore, we observed that the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway by collagen I and collagen I-induced COX-2 overexpression was abolished by PI3K and AKT inhibitors. Additionally, we showed that the cAMP response element (CRE) transcription factor is implicated. Finally, we studied COX-2 expression in an animal model, N(G)-nitro-l-arginine methyl ester hypertensive rats. In renal tissue and vascular walls, COX-2 and collagen type I content were upregulated. In summary, our results provide evidence that collagen type I increases COX-2 expression via the FAK/PI3K/AKT/cAMP response element binding protein signaling pathway.
authors.affiliation: Departamento de Fisiología, Alcala University, Madrid, Spain. matilde.alique@mssm.edu
authors.forename: Matilde
authors.initials: M
authors.lastname: Alique
authors.forename: Laura
authors.initials: L
authors.lastname: Calleros
authors.forename: Alicia
authors.initials: A
authors.lastname: Luengo
authors.forename: Mercedes
authors.initials: M
authors.lastname: Griera
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Iñiguez
authors.forename: Carmen
authors.initials: C
authors.lastname: Punzón
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
authors.forename: Manuel
authors.initials: M
authors.lastname: Rodríguez-Puyol
authors.forename: Diego
authors.initials: D
authors.lastname: Rodríguez-Puyol
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D050527:Mesangial Cells / Q000166:cytology / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D020033:Protein Isoforms; D012333:RNA, Messenger; D003094:Collagen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015232:Dinoprostone