Role of matrix metalloproteinases in the progression of renal disease

Metalloproteinases: The progression to end-stage kidney disease is accompan ied by accumulation of extracellular matrix (ECM) proteins. The degradation of ECM proteins occurs by the action of proteases, notably the matrix meta lloproteinases (MMP). MMP can be classified into four major groups, such as interstitial collagenases, gelatinases, stromelysins, and membrane-type (M T)-MMP. MMP are also involved in the regulation of cell proliferation and p ossibly of apoptosis. In the kidney, MMP are synthesized by intrinsic glome rular cells and tubular epithelial cells. Experimental data: MMP and TIMP expression is well studied in a variety of kidney disorders, particularly in diabetes mellitus and in experimental glo merulonephritis. In diabetes mellitus, an increased plasma concentration of MMP-9 was found to represent the earliest marker of diabetic kidney diseas e. In anti-Thy 1.1 nephritis, a rat model of mesangial proliferative glomer ulonephritis, an increase in proliferation of mesangial cells is associated with augmented expression of MMP-2 and accumulation of extracellular matri x proteins. These inflammatory features can be attenuated by a synthetic MM P inhibitor. Abnormal MMP and TIMP regulation: The hypothesis that MMP play an important role in the progression of nephropathies is mainly based on the well known ability of MMP to degrade ECM components, on the association of altered MM P expression in a large number of kidney diseases, and on the ability of MM P-2 to induce or to sustain an inflammatory mesangial cell phenotype. Howev er, since there are only few interventional or functional studies, uncertai nty persists as to whether abnormal regulation of MMP and TIMP represents a cause or simply an effect of the respective renal diseases. A dual role: In nephropathies, MMP appear to play a dual role as antifibrot ic enzymes and as proinflammatory mediators. The exact biologic function in a given renal disorder may depend upon the level of net MMP activity and o n the acuteness or the chronicity of the respective disease.