Physiology and pathophysiology of the plasminogen system in the kidney

The plasminogen system is important for fibrinolysis in addition to tissue remodeling and inflammation with significance for kidney disease. The system consists of the circulating zymogen plasminogen (Plg) and the tissue- and urokinase-type plasminogen activators, tPA and uPA, expressed in the glomeruli, endothelium and tubular epithelium, respectively, and the inhibitors α₂-antiplasmin and plasminogen activator inhibitor-type1, PAI-1. Plasminogen is activated by surface receptors, some with renal expression: urokinase-type plasminogen activator receptor (uPAR), plasminogen receptor KT (Plg-R_KT), and tPA, most evident in the endothelium. Plasmin may exert effects through protease-activated receptors, PARs, expressed in the kidney. Deletion of plasminogen system component genes confers no major developmental or renal phenotypes in normal mice. In glomerular injury and renal interstitial fibrosis, deletion of various components, notably Plg, uPA, PAI, and uPAR is associated with protection suggesting a disease promoting effect of plasmin, in some cases exerted through PAR1 receptor activation. Plasminogen and uPA are aberrantly filtrated across the glomerular barrier in proteinuria, and plasminogen is activated in the tubular fluid. In the tubular fluid, plasmin may activate proteolytically the epithelial sodium channel (ENaC) and inhibit the apical calcium transporter transient receptor potential cation channel subfamily V member 5 (TRPV5), which could explain impaired sodium excretion and enhanced calcium excretion in proteinuria. Amiloride, a potassium-sparing diuretic, inhibits urokinase and plasmin activation in the tubular fluid and uPAR expression in vitro, which highlights new indications for an old drug. Protease inhibitors lowered blood pressure and antagonized fibrosis in salt-sensitive Dahl rats. Current knowledge indicates that the plasminogen system aggravates renal disease by direct and indirect hypertensive effects and is a promising target to antagonize disease progression.