The mice developed progressive mesangial matrix expression, an increase in the number of mesangial cells, and an augmented immune complex deposition, together with immunoglobulins and complement. Binding and functional assays in vitro identified plasmin as a biologic substrate of megsin and confirmed the activity of megsin as a proteinase inhibitor. Transgenic mice exhibiting nephritis as a result of treatment with antiglomerular basement membrane antiserum showed significantly more persistent expansion of the mesangial extracellular matrix than was seen in control mice. The amino acid sequences in the reactive loop site of megsin showed characteristic features of functional serpins. Northern blot and RT-PCR analyses of various tissues and cells demonstrated that megsin is predominantly expressed in human mesangial cells.