PMID- 10820165
OWN - NLM
STAT- MEDLINE
DCOM- 20000810
LR  - 20210511
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 11
IP  - 6
DP  - 2000 Jun
TI  - Regenerative and proinflammatory effects of thrombin on human proximal tubular 
      cells.
PG  - 1016-1025
LID - 10.1681/ASN.V1161016 [doi]
AB  - Interstitial fibrin deposition is a common histologic feature of 
      tubulointerstitial diseases, which suggests that the coagulation system is 
      activated. Thrombin, generated during the activation of the coagulation cascade, 
      is a powerful activating factor for different cell types. Although proximal 
      tubular cells are potential targets for this coagulation factor, no information 
      is available on the effect of thrombin on these cells. Thus, the expression of 
      protease-activated receptor-1 (PAR-1), the main thrombin receptor, was 
      investigated in human proximal tubular cells (hPTC) in vivo and in vitro. A 
      diffuse expression of PAR-1 was observed by immunohistochemistry along the 
      basolateral membrane of PTC in normal human kidney. This observation was 
      confirmed in vitro in cultured hPTC. Because tubular damage and monocyte 
      infiltration are two hallmarks of tubulointerstitial injury, the effect of 
      thrombin on DNA synthesis and monocyte chemotactic peptide-1 (MCP-1) gene and 
      protein expression was evaluated in cultured hPTC. Thrombin induced a significant 
      and dose-dependent increase in thymidine uptake and a striking upregulation of 
      MCP-1 mRNA expression and protein release into the supernatant. Although PAR-1 is 
      a G protein-coupled receptor, its activation in hPTC, as in other cell systems, 
      resulted in a transient increase in cellular levels of tyrosine-phosphorylated 
      proteins. An increased level of tyrosine-phosphorylated c-src suggested the 
      activation of this cytoplasmic tyrosine kinase in response to thrombin and its 
      potential role in thrombin-induced protein-tyrosine phosphorylation. 
      Interestingly, thrombin-induced DNA synthesis and MCP-1 gene expression were 
      completely blocked by genistein, a specific tyrosine kinase inhibitor, but not by 
      its inactive analogue daidzein, demonstrating a central role for tyrosine kinase 
      activation in the thrombin effects on hPTC. Moreover, the specific src inhibitor 
      PP1 abolished the thrombin effect on DNA synthesis. In conclusion, thrombin might 
      represent a powerful regenerative and proinflammatory stimulus for hPTC in acute 
      and chronic tubulointerstitial diseases.
FAU - Grandaliano, Giuseppe
AU  - Grandaliano G
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
FAU - Monno, Raffaella
AU  - Monno R
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
FAU - Ranieri, Elena
AU  - Ranieri E
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
FAU - Gesualdo, Loreto
AU  - Gesualdo L
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
FAU - Schena, Francesco P
AU  - Schena FP
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
FAU - Martino, Carmela
AU  - Martino C
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
FAU - Ursi, Michele
AU  - Ursi M
AD  - Division of Nephrology/Department of Emergency and Transplantation, University of 
      Bari, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Chemokine CCL2)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, PAR-1)
RN  - 0 (Receptors, Thrombin)
RN  - 63231-63-0 (RNA)
RN  - 9007-49-2 (DNA)
RN  - EC 3.4.21.5 (Thrombin)
SB  - IM
MH  - Analysis of Variance
MH  - Antibodies, Monoclonal
MH  - Cell Line
MH  - Chemokine CCL2/genetics/metabolism
MH  - DNA/biosynthesis
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Gene Expression
MH  - Humans
MH  - Immunochemistry
MH  - Inflammation/physiopathology
MH  - Kidney Tubules, Proximal/drug effects/metabolism/*physiopathology
MH  - Molecular Probe Techniques
MH  - Phosphorylation
MH  - RNA/isolation & purification
MH  - RNA, Messenger/metabolism
MH  - Receptor, PAR-1
MH  - Receptors, Thrombin/*metabolism
MH  - Regeneration/physiology
MH  - Thrombin/pharmacology/*physiology
MH  - Up-Regulation
EDAT- 2000/05/23 09:00
MHDA- 2000/08/12 11:00
CRDT- 2000/05/23 09:00
PHST- 2000/05/23 09:00 [pubmed]
PHST- 2000/08/12 11:00 [medline]
PHST- 2000/05/23 09:00 [entrez]
AID - 11/6/1016 [pii]
AID - 10.1681/ASN.V1161016 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2000 Jun;11(6):1016-1025. doi: 10.1681/ASN.V1161016.