MATRIX METALLOPROTEINASE (STROMELYSIN-1) INCREASES THE ALBUMIN PERMEABILITY OF ISOLATED RAT GLOMERULI

Matrix metalloproteinases (MMPs) secreted by connective tissue cells a re capable of acting on extracellular matrix components of glomerular basement membrane at a slow rate and thus may play a role in the contr ol of protein permeability and in the progression of certain kinds of glomerulonephritis. We have used an in vitro assay to measure the dire ct effect of three MMPs and human neutrophil elastase on glomerular al bumin permeability (P-albumin). Glomeruli were isolated from normal ma le Sprague-Dawley rats and suspended in isolation medium with or witho ut interstitial collagenase, gelatinase-A, stromelysin-1, or elastase and were incubated at 37 degrees C for up to 4 hours. A tissue-specifi c inhibitor of matrix metalloproteinases (TIMP-1) and a plasma protein ase inhibitor, alpha(2)-macroglobulin (alpha(2)M), were used to block the activity of MMPs. P-albumin was calculated from the change in glom erular volume in response to an applied oncotic gradient. In this stud y stromelysin-1 (10 mu g/ml) and elastase (5 mu g/ml) increased P-albu min significantly. Stromelysin-1 increased P-albumin after 4 hours, wh ereas elastase had an effect after 2 hours. Lower concentrations of st romelysin-1 or shorter incubation time had no effect on P-albumin. Inc ubation for up to 4 hours with interstitial collagenase (10 mu g/ml) o r gelatinase-A (10 mu g/ml) had no effect on P-albumin. Coincubation w ith TIMP-1 and alpha(2)M blocked the stromelysin-1-mediated increase i n P-albumin. We conclude that stromelysin-1 is capable of affecting th e glomerular filtration barrier directly and that it may play an impor tant role in causing proteinuria in glomerular diseases.