Thrombin Down-Regulates the TGF-β-Mediated Synthesis of Collagen and Fibronectin by Human Proximal Tubule Epithelial Cells Through the EPCR-Dependent Activation of PAR-1

摘要

Human proximal tubule (HK-2) cells are commonly used as cellular models to understand the mechanism by which inflammatory mediators cause renal injury. It has been observed that thrombin stimulates the expression of TGF-β, extracellular matrix (ECM) proteins and proinflammatory cytokines by HK-2 cells. These in vitro responses correlate well with the pathology of glomerular and tubular diseases observed in acute renal injury. HK-2 cells express PAR-1 and the thrombin activation of this receptor has been reported to up-regulate the TGF-β-mediated expression of ECM proteins, suggesting a possible pathogenic role for PAR-1 signaling by thrombin in acute renal injury. On the other hand, several recent studies have indicated that activated protein C plays a renoprotective role, thus inhibiting the inflammatory responses and attenuating renal injury, presumably by activating the same cell surface receptor. In this study, we show that HK-2 cells express endothelial protein C receptor (EPCR) and that the occupancy of this receptor by protein C switches the signaling specificity of thrombin so that the activation of PAR-1 by thrombin inhibits the TNF-α-mediated synthesis of IL-6 and IL-8 and down-regulates the TGF-β-mediated expression of ECM proteins. These results suggest a possible protective role for EPCR in acute kidney injury.