Proteolytic enzymes as mediators of glomerular injury

Despite significant advances in our understanding of the pathogenesis of glomerular injury, the specific mechanisms responsible for the pathological changes in glomerular structure and function which occur in glomerular disease remain poorly understood. Several diverse lines of evidence, including studies with purified proteinases, studies with freshly isolated glomeruli and intact cells, and cells in culture, as well as recent in vivo studies indicate that proteolytic enzymes play important roles as mediators of glomerular injury. The concept of proteolytic enzymes as mediators of glomerular injury is not new. The ability of polymorphonuclear leukocyte (PMN)-derived proteinases to degrade glomerular basement membrane (GBM) in vitro coupled with the PMN-dependence of certain types of glomerulonephritis led Cochrane and coworkers in the mid-sixties to postulate that neutrophil-derived proteinases cause glomerular injury by proteolysis of the GBM [1–3]. Since then, a large number of studies have provided support for this hypothesis. In addition, recent studies documenting the presence of GBM-degrading proteinases in glomeruli, plasma, and a variety of other circulating cells indicate that GBM damage can also be mediated by proteinases originating from these sources as well. Thus proteinase-mediated GBM damage may be an important mechanism of glomerular injury in leukocyte-independent as well as leukocyte-dependent glomerular diseases. Furthermore, recent studies suggest that proteolytic enzymes may contribute to glomerular injury by mechanisms independent of GBM damage. Such mechanisms include: proteolysis of non-GBM proteins; proteinase-mediated alterations in the production of key glomerular metabolites; and proteinase-induced effects on cellular proliferation. In the present review, we attempt to bring together a large body of diverse information derived from in vitro and in vivo studies, which supports a pathogenic role for proteolytic enzymes in glomerular injury.