LPS INDUCES MAJOR CHANGES IN THE EXTRACELLULAR PROTEOLYTIC BALANCE INTHE MURINE KIDNEY

Recent investigations have shown that in the murine kidney urokinase ( uPA) and tissue-type plasminogen activator (tPA) are synthesized and r eleased in urine by tubular epithelial cells, raising the possibility that plasminogen activators (PAs) may be involved in the maintenance o f patency and fluidity in renal tubules. To further investigate the co ntribution of the PA system in renal pathology, we have determined the effects of LPS on the renal production of PAs: we localized PA-cataly zed proteolysis by zymographic analysis of tissue sections and studied the accumulation of mRNAs for PAs and their inhibitors (PAI-1 and PAI -2) by in situ hybridization. Both a single and two injections of LPS induced a dramatic reduction in urinary and renal uPA enzymatic activi ty; this decrease in catalytic activity was attributable to a reductio n in uPA mRNA levels in both proximal and distal tubules. By contrast, we noticed a marked increase of tPA mRNA content in glomerular cells which was not accompanied by a concomitant increase in tPA-mediated pr oteolytic activity. In addition, a major up-regulation in PAI-1 mRNA l evels was observed throughout the kidney, while PAI-2 mRNA was not det ectable in the kidneys of control or LPS-injected animals. Our investi gations document the profound alterations of the PA/PAI balance in ren al tissue following in vivo LPS administration. They suggest that imba lanced extracellular proteolysis might participate in the alterations of kidney function observed in septic shock.