Tissue plasminogen activator and chronic kidney disease: More than a simple protease

Tissue plasminogen activator (tPA) is a member of the serine protease family that plays a pivotal role in the homeostasis of blood coagulation/fibrinolysis and matrix regulation. It is the FDA-approved first choice for embolic diseases such as ischemic stroke and acute myocardial infarction. However, its clinical usage has been significantly damped by its nonprotease-related side effects and toxicity. Recent studies discovered that tPA is a hybrid molecule with dual functions: protease and cytokine. As a protease, tPA converts plasminogen into active plasmin and participates in the fibrinolysis and matrix degradation. As a cytokine, tPA activates numerous receptor-mediated cellular signal transduction events contributing to its undesirable side effects and toxicity. tPA, as a cytokine, plays a detrimental role in the pathogenesis of chronic kidney disease (CKD) through multiple molecular mechanisms: 1) induces matrix metalloproteinases production through MAPK pathway triggering the epithelial mesenchymal transition; 2) promotes the survival, proliferation, and interstitial accumulation of fibroblasts in the diseased kidneys through p90RSK signaling; 3) promotes myofibroblast activation and macrophage migration by activating integrin signals; 4) modulates inflammation via NF-?B activation. This chapter will discuss the role of tPA and its receptormediated signaling cascades in the pathogenesis and progression of CKD.