Matrix metalloproteinases and TIMPS in cultured C57BL/6J-cpk kidney tubules

Restructuring of basement membranes is a hallmark of the pathology of renal cystic disorders. Here, we present findings consistent with the view that basement membrane degradation by matrix metalloproteinases (MMPs) may contribute to abnormal basement membrane structure in polycystic kidney disease. Cells from cystic kidney tubules embedded in collagen gels appeared to migrate through the gel. This migration through collagen indicated that these cells could degrade the matrix. To examine this activity, wt: cultured cystic kidney tubules derived from the C57BL/6J cpk/cpk mouse, a hereditary modal of polycystic kidney disease, and assayed conditioned medium for the presence of MMPs and tissue inhibitors of metalloproteinases (TIMPs). The conditioned medium from the cystic tubules contained higher than normal levels of MMP-9, MMP-2, and MMP-3 as well as TIMP-1 and TIMP-2. A 101 kDa protease was present equally in cystic and control cultures and although inhibited by EDTA, it was not inhibited by TIMPs, nor activated by the mereurial compound APMA. These data suggest that cystic kidney tubules synthesize and secrete high levels of MMPs which may then participate in the restructuring of the tubular basement membrane.