Thrombin down-regulates the TGF-beta-mediated synthesis of collagen and fibronectin by human proximal tubule epithelial cells through the EPCR-dependent activation of PAR-1.
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-beta, 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-beta-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-alpha-mediated synthesis of IL-6 and IL-8 and down-regulates the TGF-beta-mediated expression of ECM proteins. These results suggest a possible protective role for EPCR in acute kidney injury.
Bae
Jong-Sup
JS
Department of Herbal Pharmaceutical Engineering, College of Herbal Bio-Industry, Daegu Haany University, Gyeongsangbuk-do, Republic of Korea. baejs@dhu.ac.kr
Kim
In-San
IS
Rezaie
Alireza R
AR
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011486:Protein C / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D015703:Antigens, CD; D024141:Collagen Type IV; D000074283:Endothelial Protein C Receptor; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D015850:Interleukin-6; D016209:Interleukin-8; C478370:PROCR protein, human; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D013917:Thrombin