Regulated expression of matrix metalloproteinases and TIMP in nephrogenesis.

The roles of the matrix metalloproteinases (MMPs) and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMP), in embryologic development in general, and in nephrogenesis in particular, have not been fully elucidated. The activities of these enzymes and their inhibitors may be critical in the extensive extracellular matrix remodeling that accompanies the formation of the full complement of mature nephrons in the developing kidney. The temporal and spatial expression of two critical basal lamina modifying enzymes, the 72 kDa gelatinase A (MMP-2) and the 92 kDa gelatinase B (MMP-9), as well as TIMP-1, -2, and -3 molecules were evaluated in the developing rat kidney. Additionally, transcripts for the recently described membrane-associated matrix metalloproteinase, MT1-MMP (MMP-14), which can act as an activating receptor for MMP-2/TIMP-2 complexes (Strongin et al.[1995] J. Biol. Chem. 270:5331-5338) were localized by in situ hybridization. Our immunohistochemical data demonstrate distinct localization of MMP-2 within immature nephron structures undergoing epithelial differentiation, while MMP-9 localizes only to the invading vascular structures within immature glomeruli. In contrast, by in situ hybridization, MMP-2 transcripts localize to the background undifferentiated mesenchyme and not to those structures undergoing epithelial differentiation. In a pattern similar to the MMP-2 protein, MT1-MMP transcripts were found within developing epithelial structures. Neither MMP-2, MMP-9 nor MT1-MMP were detected in mature nephrons. TIMP-2 and -3 follow a pattern of expression similar to the MMP-2 protein. We conclude that MMP-2 and TIMP play important roles in the remodeling of basal laminae associated with the epithelial structures of the developing kidney, that these enzymes are temporally and spatially regulated, and that the co-localization of MT1-MMP to sites of basement membrane remodeling suggests a potential role for this molecule as a receptor for and/or modulator of MMP-2/TIMP complexes.