Matrix metalloproteinase (MMP)9/gelatinase B is increased in various nephropathies. To investigate its role, we used a genetic approach. Adult MMP9-deficient (MMP9−/−) mice showed normal renal histology and function at 3 mo. We investigated the susceptibility of 3-mo-old mice to the accelerated model of anti-glomerular basement membrane nephritis, in which fibrin is an important mediator of glomerular injury and renal impairment. Unexpectedly, nephritis was more severe in MMP9−/− than in control mice, as attested by levels of serum creatinine and albuminuria, and the extent of crescents and fibrin deposits. Circulating or deposited immunoglobulin G, interleukin (IL)-1β, or IL-10 were the same in MMP9−/− and MMP9+/+ mice. However, we found that fibrin is a critical substrate for MMP9, and in its absence fibrin accumulated in the glomeruli. These data indicate that MMP9 is required for a novel protective effect on the development of fibrin-induced glomerular lesions.

The transcription of type I collagen genes is tightly regulated, but few cis-acting elements have been identified that can modulate the levels of expression of these genes. Generation of transgenic mice harboring various segments of the mouse pro-␣1(I) collagen promoter led us to suspect that a repressor element was located between ؊10.5 and ؊17 kilobase pairs. Stable and transient transfection experiments in ROS17/2.8 osteoblastic cells confirmed the existence of such a repressor element at about ؊14 kilobase pairs and showed that it consisted in an almost perfect three-time repeat of a 41-base pair sequence. This element, which we named COIN-1, contains three E2-boxes, and a point mutation in at least two of them completely abolished its repressor effect. In gel shift assays, COIN-1 bound a DNAbinding protein named ␦EF1/ZEB-1, and mutations that abolished the repressor effect of COIN-1 also suppressed the binding of ␦EF1. We also showed that the repressor effect of COIN-1 was not mediated by chromatin compaction. Furthermore, overexpression of ␦EF1 in ROS17/ 2.8 osteoblastic cells enhanced the inhibitory effect of COIN-1 in a dose-dependent manner and repressed the expression of the pro-␣1(I) collagen gene. Thus, ␦EF1 appears to repress the expression of the mouse pro-␣1(I) collagen gene, through its binding to COIN-1.Type I collagen is a fibrillar collagen composed of two ␣1 chains and one ␣2 chain coiled around each others in a triple helix. It is the most abundant protein of mammalian bodies, and a major component of most extracellular matrices. In the extracellular space, type I collagen molecules self-assemble into highly organized fibrils and then fibers, which largely contribute to the high tensile strength of the structural framework supporting body structures (reviewed in Ref.

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