title: Aristolochic acid downregulates monocytic matrix metalloproteinase-9 by inhibiting nuclear factor-κB activation.
abstract: Aristolochic acid (AA)-associated nephropathy was described as being characterized by a rapid progressive enhancement of interstitial renal fibrosis. Renal tissue fibrosis occurs because of an imbalance of extracellular matrix (ECM) accumulation and matrix metalloproteinase (MMP) activation. Much evidence indicates that inflammatory renal disease including monocyte and mesangial interactions is linked to the development and progression of renal remodeling. In this study, we found that AA showed concentration-dependent inhibition of tumor necrosis factor (TNF)-α-induced MMP-9 activation with an IC(50) value of 6.4±0.5μM in human monocytic THP-1 cells. A similar effect was also noted with different ratios of AAs (types I and II). However, AA had no inhibitory effect on the intact enzymatic activity of MMP-9 at a concentration of 20μM. On the other hand, the level of tissue inhibitor of metalloproteinase (TIMP)-1 was not induced by AA, but it suppressed TNF-α-induced MMP-9 protein and messenger RNA expressions. AA also significantly inhibited TNF-α-induced IκBα degradation. Furthermore, an electrophoretic mobility shift assay and a reported gene study, respectively, revealed that AA inhibited TNF-α-induced NF-κB translocation and activation. In addition, compared to other NF-κB inhibitors, AA exerted significant inhibition of MMP-9 activation and monocyte chemotactic protein-1-directed invasion. From these results, we concluded that AA, a natural compound, inhibits TNF-α-induced MMP-9 in human monocytic cells possibly through the NF-κB signal pathway. These results also imply that AA may be involved in alteration of matrix homeostasis during renal fibrosis in vivo.
authors: Division of Nephrology, Mackay Memorial Hospital and Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
authors: Chih-Jen
authors: CJ
authors: Wu
authors: Yung-Chen
authors: YC
authors: Chou
authors: Yu-Wen
authors: YW
authors: Cheng
authors: Che-Jen
authors: CJ
authors: Hsiao
authors: Chen-Hsu
authors: CH
authors: Wang
authors: Hsin-Yu
authors: HY
authors: Wang
authors: Joen-Rong
authors: JR
authors: Sheu
authors: George
authors: G
authors: Hsiao
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity*; D034341:Aristolochic Acids / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000633:toxicity; D006801:Humans; D007668:Kidney / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D034341:Aristolochic Acids; D004365:Drugs, Chinese Herbal; D016328:NF-kappa B; D019715:Tissue Inhibitor of Metalloproteinase-1; C000228:aristolochic acid I; D020780:Matrix Metalloproteinase 9