title: TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury.
abstract: Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2, whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts, and solute carriers. Renal injury in TIMP3(-/-), but not in TIMP2(-/-), mice increased the expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β, and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3(-/-) mice, which was completely blocked in the kidneys of TIMP2(-/-) mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3(-/-) and its reduction in TIMP2(-/-) mice. The activities of tumor necrosis factor-α-converting enzyme, caspase-3, and mitogen-activated kinases were elevated in the kidneys of TIMP3(-/-) mice but not TIMP2(-/-) mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3(-/-) mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury: TIMP3 protects from damage, whereas TIMP2 promotes injury through MMP2 activation.
authors.affiliation: 1] Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada [2] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Konrad
authors.initials: K
authors.lastname: Famulski
authors.affiliation: 1] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada [2] Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Lee
authors.affiliation: 1] Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada [2] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Subhash K
authors.initials: SK
authors.lastname: Das
authors.affiliation: 1] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada [2] Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Halloran
authors.affiliation: 1] Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada [2] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada [3] Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
authors.affiliation: 1] Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada [2] Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014517:Ureteral Obstruction
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D019716:Tissue Inhibitor of Metalloproteinase-2; D051722:ADAM Proteins; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D000072198:ADAM17 Protein