LPS induces major changes in the extracellular proteolytic balance in the murine kidney

Recent investigations have shown that in the murine kidney urokinase (uPA) and tissue-type plasminogen activator (tPA) are synthesized and released in urine by tubular epithelial cells, raising the possibility that plasminogen activators (PAs) may be involved in the maintenance of patency and fluidity in renal tubules. To further investigate the contribution of the PA system in renal pathology, we have determined the effects of LPS on the renal production of PAs: we localized PA-catalyzed 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 activity; this decrease in catalytic activity was attributable to a reduction 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 proteolytic activity. In addition, a major up-regulation in PAI-1 mRNA levels was observed throughout the kidney, while PAI-2 mRNA was not detectable in the kidneys of control or LPS-injected animals. Our investigations document the profound alterations of the PA/PAI balance in renal tissue following in vivo LPS administration. They suggest that imbalanced extracellular proteolysis might participate in the alterations of kidney function observed in septic shock.