Role of matrix metalloproteinase-9 (MMP-9) in kidney development and injury

Matrix metalloproteinase-9 (MMP-9) has a restricted pattern of expression in developmental and adult tissues. Its principal substrate is type IV collagen but it can degrade other basement membrane molecules, as well as substrates that are not matrix components. We have previously shown that MMP-9 is produced at the first stage of kidney embryogenesis in vivo and is required for branching morphogenesis in vitro [Lelongt B, Trugnan G, Murphy G, Ronco PM: Matrix metalloproteinases MMP2 and MMP9 are produced in early stages of kidney morphogenesis but only MMP9 is required for renal organogenesis in vitro. J Cell Biol 137:1-11, 1997]. We took advantage of the availability of MMP-9-deficient mice to analyze their renal phenotype under physiologic condition and in a model of acute renal failure. MMP-9-deficient mice are actually viable, suggesting the absence of major kidney defects. However, we did observe two renal abnormalities. First, MMP-9-deficient adult mice have a 15% reduction of nephron number that most likely results from subtle defects of branching morphogenesis and a marked increase in mesenchymal apoptosis. Second, 12-month-old deficient mice develop renal impairment and atrophy compared to control mice. This is most likely explained by superimposition on nephron loss of histologic lesions characterized by an increased interstitial deposition of extracellular matrix associated with inflammatory cell infiltration as compared to control kidneys. This mild, but highly significant phenotype, is in the same order of magnitude as the one observed in long bones [Vu TH, Shipley JM, Bergers G, et al: MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93:411-422, 1998]. We then asked whether the antiapoptotic role of MMP-9 observed during renal development could extend to renal pathology. Since there is no renal alteration in 3-month-old MMP-9-deficient mice, we used those mice and control mice to induce an acute renal failure by intraperitoneal injection of folic acid. This model is characterized by an apoptotic phase 12 to 24 hours after the folic acid injection [Ortiz A, Lorz C, Catalan MP, et al: Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure. Kidney Int 57:969-981, 2000]. Therefore, we compared kidneys from MMP-9-deficient mice and control mice 18 hours after folic acid injection. Both groups of mice developed renal failure of equal severity. MMP-9 activity was markedly increased in control mice, suggesting an effect of this enzyme. Indeed, renal lesions were more severe in MMP-9-deficient mice in which the number of dilated tubules was increased and the number of apoptotic cell was raised by two- to threefold in cortex, medulla, and papilla. In summary, MMP-9-deficient mice exhibit increased extent of apoptosis in the folic acid model of acute renal failure as well as in kidney development. We are currently investigating the MMP-9 antiapoptotic mode of action