Inhibition of matrix metalloproteinases attenuates anti-Thy1.1 nephritis.

There is accumulating evidence that matrix ruetalbo- proteinases (MMP) play a prominent role in gboruerular inflaru- matory diseases. The aim of the present study was to determine the anti-inflammatory effects of the synthetic MMP inhibitor BB-l 101 in acute anti-Thyl.l nephritis. Sixty-three male Wistar rats were studied: healthy rats (ii 9), treated healthy rats ('1 = 9), nephritic rats (ii = 18). and treated nephritic rats (ii = 27). BB-llOl therapy (30 rug/kg body wt per d) of nephritic animals was initiated either 2 d before (n = I 8) or 2 d after (ii = 9) disease induction. Renal histology was analyzed 1 1 d after induction of the ncphritis, at the peak of MMP-2 production and total gbomerular cellularity. Pretreatment of nephritic rats by BB-l 101 resulted in a significant amelioration of gbomerubar histology, assessed by gboruerular cellularity, extracellubar matrix deposition, and size of gbomerubar cross- sections. These beneficial effects were less pronounced, but in part still significant, in animals treated by BB-b 101 after in- duction of anti-Thy I. 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 treat- ruent. 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 syn- thetic compounds may represent a new approach to the therapy of ruesangial cell-mediated forms of gbomerubonephritis. (I Am Soc Nephrol 9: 397-407, 1998)