Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation

@article{citeulike:2822349, abstract = {Background. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with renal fibrosis. Furthermore, it is a multi-functional protein, and whether it has other roles in renal fibrosis is unknown. As several inflammatory mediators are substrates of matrix metalloproteinases (MMPs), TIMP-1 might affect renal fibrosis via inflamatory pathways. Methods. Plasmids containing the sense and antisense human TIMP-1 sequence were stably transfected into the human kidney proximal tubular epithelial cell line (HKC), MMP-2 and MMP-9 siRNA were transiently transfected into HKC and the transfected cells were stimulated with phorbol 12-myristate 13-acetate (PMA). In vivo, we established unilateral ureteral obstruction (UUO) models by using homozygote human TIMP-1 transgenic mice. The expression of intercellular adhesion molecule-1 (ICAM-1) in transfected cells and F4/80-positive cells in the renal interstitium were examined by indirect immunofluorescence. Protein levels in the cells and UUO models were examined by western blot, and the activities of the gelatinases and TIMP-1 were examined by gelatin zymography and reverse zymography, respectively. Results. After stimulation with PMA, the activities of the gelatinases were decreased, ICAM-1 was upregulated, and soluble ICAM-1 in the supernatant was decreased, in HKC transfected with sense TIMP-1, and ICAM-1 was increased in HKC transfected with MMP-9 siRNA. At 14 days after UUO, it was found that compared with wild-type mice, in transgenic mice, with upregulation of TIMP-1, activities of gelatinases were downregulated, ICAM-1, transforming growth factor-1 (TGF-1), collagens I and III were upregulated, and the extent of renal fibrosis and infiltration of macrophages was more severe. Conclusion. Overexpression of TIMP-1 could promote renal interstitial fibrosis through the inflammatory pathway, which might be partly induced by upregulating ICAM-1. 10.1093/ndt/gfm666}, author = {Cai, Guangyan and Zhang, Xueguang and Hong, Quan and Shao, Fengmin and Shang, Xiyao and Fu, Bo and Feng, Zhe and Lin, Hongli and Wang, Jianzhong and Shi, Suozhu and Yin, Zhong and Chen, Xiangmei }, citeulike-article-id = {2822349}, doi = {10.1093/ndt/gfm666}, journal = {Nephrol. Dial. Transplant.}, keywords = {ckd, fibrosis}, month = {June}, number = {6}, pages = {1861--1875}, posted-at = {2008-05-22 07:00:05}, priority = {2}, title = {Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation}, url = {http://dx.doi.org/10.1093/ndt/gfm666}, volume = {23}, year = {2008} }

TY - JOUR ID - citeulike:2822349 L3 - citeulike-article-id:2822349 TI - Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation JF - Nephrol. Dial. Transplant. VL - 23 IS - 6 SP - 1861 EP - 1875 N2 - Background. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is associated with renal fibrosis. Furthermore, it is a multi-functional protein, and whether it has other roles in renal fibrosis is unknown. As several inflammatory mediators are substrates of matrix metalloproteinases (MMPs), TIMP-1 might affect renal fibrosis via inflamatory pathways. Methods. Plasmids containing the sense and antisense human TIMP-1 sequence were stably transfected into the human kidney proximal tubular epithelial cell line (HKC), MMP-2 and MMP-9 siRNA were transiently transfected into HKC and the transfected cells were stimulated with phorbol 12-myristate 13-acetate (PMA). In vivo, we established unilateral ureteral obstruction (UUO) models by using homozygote human TIMP-1 transgenic mice. The expression of intercellular adhesion molecule-1 (ICAM-1) in transfected cells and F4/80-positive cells in the renal interstitium were examined by indirect immunofluorescence. Protein levels in the cells and UUO models were examined by western blot, and the activities of the gelatinases and TIMP-1 were examined by gelatin zymography and reverse zymography, respectively. Results. After stimulation with PMA, the activities of the gelatinases were decreased, ICAM-1 was upregulated, and soluble ICAM-1 in the supernatant was decreased, in HKC transfected with sense TIMP-1, and ICAM-1 was increased in HKC transfected with MMP-9 siRNA. At 14 days after UUO, it was found that compared with wild-type mice, in transgenic mice, with upregulation of TIMP-1, activities of gelatinases were downregulated, ICAM-1, transforming growth factor-1 (TGF-1), collagens I and III were upregulated, and the extent of renal fibrosis and infiltration of macrophages was more severe. Conclusion. Overexpression of TIMP-1 could promote renal interstitial fibrosis through the inflammatory pathway, which might be partly induced by upregulating ICAM-1. 10.1093/ndt/gfm666 KW - ckd KW - fibrosis AU - Cai, Guangyan AU - Zhang, Xueguang AU - Hong, Quan AU - Shao, Fengmin AU - Shang, Xiyao AU - Fu, Bo AU - Feng, Zhe AU - Lin, Hongli AU - Wang, Jianzhong AU - Shi, Suozhu AU - Yin, Zhong AU - Chen, Xiangmei PY - 2008/06/01/ UR - http://dx.doi.org/10.1093/ndt/gfm666 ER -