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

Jong Sup Bae, In-San Kim, Alireza R. Rezaie

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 upregulate 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 downregulates the TGF-β-mediated expression of ECM proteins. These results suggest a possible protective role for EPCR in acute kidney injury.

Original languageEnglish
Pages (from-to)233-239
Number of pages7
JournalJournal of Cellular Physiology
Volume225
Issue number1
DOIs
Publication statusPublished - 2010 Oct 1
Externally publishedYes

Fingerprint

Protein C
Fibronectins
Thrombin
Extracellular Matrix Proteins
Collagen
Down-Regulation
Epithelial Cells
Chemical activation
Acute Kidney Injury
Thrombin Receptors
Kidney
Wounds and Injuries
Cell Surface Receptors
Interleukin-8
Endothelial cells
Pathology
Interleukin-6
Up-Regulation
Cytokines
Switches

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

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abstract = "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 upregulate 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 downregulates the TGF-β-mediated expression of ECM proteins. These results suggest a possible protective role for EPCR in acute kidney injury.",
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