NDT Advance Access originally published online on March 8, 2008
Nephrology Dialysis Transplantation 2008 23(6):1861-1875; doi:10.1093/ndt/gfm666
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Tissue inhibitor of metalloproteinase-1 exacerbated renal interstitial fibrosis through enhancing inflammation
Department of Nephrology, Institute of Nephrology & Key Lab of PLA, Chinese General Hospital of PLA, Fuxing Road 28, Beijing, P.R. China
Correspondence and offprint requests to: Correspondence and offprint requests to: Xiangmei Chen, MD, PhD, Department of Nephrology, Institute of Nephrology and Key Lab of PLA, Chinese General Hospital of PLA, Fuxing Road 28, Beijing 100853, P.R. China. Tel: +86-10-66937011; Fax: +86-10-68130297; E-mail: xmchen301{at}126.com
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Abstract |
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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-β1 (TGF-β1), 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.
Keywords: inflammation; intercellular adhesion molecule-1; renal fibrosis; tissue inhibitor of metalloproteinase-1; transgene
Received for publication: 12. 4.06
Accepted in revised form: 27. 8.07