Inhibitory effect of interleukin-) on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells

摘要

First published November 7, 2007; doi:10.1152/ajprenal.00129.2007.-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 TV collagen. During renal injury, ANG II and the macrophage-produced cytokine interleu-kin-1beta (IL-1beta may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between ANG II and -1beta in renal fibrosis. For this reason, in cultured mesangial cells (MC), we investigated whether IL-1beta could regulate ANG H-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. ILbeta did not increase the production of CTGF and type TV collagen but significantly inhibited ANG II-induced CTGF and type IV collagen over-expression. Moreover, IL-1beta also inhibited type TV collagen upregulation caused by exogenous recombinant CTGF. Matrix metallopro-teinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of ILbeta and ANG II caused a synergistic increase in MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-beta 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 downregu-lation, 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.