title: Inhibitory effect of interleukin-1beta on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells.
abstract: Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix accumulation. Angiotensin II (ANG II) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and extracellular matrix proteins, such as type IV collagen. During renal injury, ANG II and the macrophage-produced cytokine interleukin-1beta (IL-1beta) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between ANG II and IL-1beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we investigated whether IL-1beta could regulate ANG II-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by ANG II. IL-1beta did not increase the production of CTGF and type IV collagen but significantly inhibited ANG II-induced CTGF and type IV collagen overexpression. Moreover, IL-1beta also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1beta and ANG II caused a synergistic increase in MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-1beta effects were dependent on activation of ERK/MAPK but independent p38-MAPK, JNK, phosphatidylinositol 3-kinase/Akt, and Rho-associated kinase pathways. In summary, these data indicate that IL-1beta inhibited ANG II-mediated type IV collagen production, via CTGF downregulation, and increased type IV collagen degradation, through MMP-9 upregulation. Our in vitro data show that the proinflammatory cytokine IL-1beta abrogates ANG II-induced CTGF production, describing antagonistic activities of proinflammatory cytokines on ANG II actions.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Díaz, Universidad Autónoma Madrid, Madrid, Spain.
authors.forename: Elsa
authors.initials: E
authors.lastname: Sánchez-López
authors.forename: Juan
authors.initials: J
authors.lastname: Rodriguez-Vita
authors.forename: Cecile
authors.initials: C
authors.lastname: Cartier
authors.forename: Monica
authors.initials: M
authors.lastname: Rupérez
authors.forename: Vanesa
authors.initials: V
authors.lastname: Esteban
authors.forename: Gisselle
authors.initials: G
authors.lastname: Carvajal
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrígues-Díez
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Plaza
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism*; D055513:Connective Tissue Growth Factor; D004357:Drug Synergism; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D024141:Collagen Type IV; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9