Physiology and pathophysiology of the plasminogen system in the kidney

Abstract

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 α-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), 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.

Inhibiting the urokinase‐type plasminogen activator receptor system recovers STZ‐induced diabetic nephropathy

“…This is also in line with the present finding that UPARANT‐induced recovery of altered vascular permeability is established through restored levels of tight junction proteins and inhibition of VEGF production. These results together suggest an additional mechanism through which the uPAR pathway negatively affects glomerular filtration and are in line with previous findings demonstrating that deletion of various components of the uPA/uPAR system is protective against vascular changes in models of renal diseases . Recovered vascular permeability is associated with UPARANT‐induced increase of AQP2 in the medulla in which AQP2 seems to prevent excessive water loss through urine .…”

“…Plg is mainly synthesized in the liver, circulates in the plasma and is activated to plasmin by a finely tuned balance between activators, including uPA, and inhibitors: a dysregulation of this system is reported in renal diseases, including DN, but the mechanisms through which it contributes to diabetic kidney lesions are not still completely understood . The present finding that UPARANT recovers, at least in part, plasmin activity is indicative of the possibility that the drug may reinstate the physiological balance between activators and inhibitors, thus reactivating the proteolytic cascade that leads to the degradation of ECM components.…”

“…Major players in the diabetes‐associated renal fibrosis include members of the plasminogen (Plg)‐plasmin system that consists of the circulating zymogen Plg and its activators including the urokinase‐type plasminogen activator (uPA), a secreted protease that, through the binding to its receptor (uPAR), converts Plg into plasmin that promotes ECM degradation either directly or indirectly through the activation of metalloproteinases (MMPs) . uPA is a secreted protease, while uPAR is expressed by glomerular cells, resident fibroblasts and cells of the collecting ducts . In rodent models of DN, uPA and uPAR are both up‐regulated in glomerular cells including podocytes suggesting that dysfunction of the uPA/uPAR system may be associated with kidney disease .…”

“…In rodent models of DN, uPA and uPAR are both up‐regulated in glomerular cells including podocytes suggesting that dysfunction of the uPA/uPAR system may be associated with kidney disease . In contrast, uPA or uPAR deletion results in protective effects against kidney injuries …”

“…8 uPA is a secreted protease, while uPAR is expressed by glomerular cells, resident fibroblasts and cells of the collecting ducts. 9 In rodent models of DN, uPA and uPAR are both up-regulated in glomerular cells including podocytes suggesting that dysfunction of the uPA/uPAR system may be associated with kidney disease. 10 In contrast, uPA or uPAR deletion results in protective effects against kidney injuries.…”