Inhibition of matrix metalloproteinases attenuates anti-Thy 1.1 Nephritis

Inselspital, Universitätsspital Bern, Berna, Bern, Switzerland
Journal of the American Society of Nephrology (Impact Factor: 9.34). 03/1998; 9(3):397-407.
Source: PubMed


There is accumulating evidence that matrix metallo-proteinases (MMP) play a prominent role in glomerular inflammatory diseases. The aim of the present study was to determine the anti-inflammatory effects of the synthetic MMP inhibitor BB-1101 in acute anti-Thy1.1 nephritis. Sixty-three male Wistar rats were studied: healthy rats (n = 9), treated healthy rats (n = 9), nephritic rats (n = 18), and treated nephritic rats (n = 27). BB-1101 therapy (30 mg/kg body wt per d) of nephritic animals was initiated either 2 d before (n = 18) or 2 d after (n = 9) disease induction. Renal histology was analyzed 11 d after induction of the nephritis, at the peak of MMP-2 production and total glomerular cellularity. Pretreatment of nephritic rats by BB-1101 resulted in a significant amelioration of glomerular histology, assessed by glomerular cellularity, extracellular matrix deposition, and size of glomerular cross-sections. These beneficial effects were less pronounced, but in part still significant, in animals treated by BB-1101 after induction of anti-Thy1.1 nephritis. Proteinuria, expressed as area under the curve of the protein:creatinine ratio versus time, was clearly decreased in both groups of treated nephritic rats. Healthy control rats were not affected by MMP inhibitor treatment. In summary, the present study demonstrates for the first time in vivo that mesangial cell proliferation can be effectively suppressed by MMP inhibition. Thus, MMP inhibition by synthetic compounds may represent a new approach to the therapy of mesangial cell-mediated forms of glomerulonephritis.

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    • "As stated above, the relative contribution of increased synthesis and decreased degradation of collagen IV to ECM accumulation remains undetermined. Studies showing that MMP inhibition attenuates ECM accumulation in rat allograft nephropathy [62], anti-Thy 1.1 nephritis [63] and other experimental inflammatory renal diseases would suggest that matrix degradation plays at least some role in this process. As discussed below, there are also indications that the MMPs confer proliferative stimuli upon mesangial cells, providing another factor that might explain an increase in MMP activity in the face of nephritis and matrix proliferation [64]. "
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    • "Anti-Thy 1.1 nephritis is characterized by an initial phase of complement-dependent mesangiolysis lasting for approximately 2 days, followed by a marked proliferative response of the residual mesangial cells associated with the accumulation of ECM [47]. We observed in preliminary experiments that the latter two features were reached at day 11 [48]. Therefore, this time point was chosen for nephrectomy and subsequent meprinβ immunostaining (Fig. 6). "
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