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Perit Dial Int 26(3): 393-401 2006
© 2006 International Society for Peritoneal Dialysis
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Basic

ENDOTHELINB RECEPTOR BLOCKER INHIBITS HIGH GLUCOSE-INDUCED SYNTHESIS OF FIBRONECTIN IN HUMAN PERITONEAL MESOTHELIAL CELLS

Miyuki Shimizu1,2, Yoshitaka Ishibashi1, Fumika Taki1, Hideki Shimizu1, Ichiro Hirahara1,2, Shinya Kaname1 and Toshiro Fujita1

Division of Total Renal Care Medicine,1 Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo; Terumo Corporation R&D Center,2 Kanagawa, Japan

Correspondence to: S. Kaname, Division of Total Renal Care Medicine, Department of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655 Japan.kaname-tky{at}umin.ac.jp

{diamondsuit} Background: Long-term peritoneal dialysis using glucose-based dialysates is associated with peritoneal fibrosis. The object of this study was to investigate the hypothesis that endothelin (ET)-1, which is known to play an important role in various fibrotic diseases, may also be involved in peritoneal fibrosis using human peritoneal mesothelial cells (HPMC).

{diamondsuit} Methods: HPMC were cultured with 4% D- or L-glucose, or loaded with 10 nmol/L ET-1. In some experiments, the ETA receptor antagonist BQ-123, the ETB receptor antagonist BQ-788, and antioxidants 4-hydroxy-2,2,6,6-tetramethyl-piperidine 1-oxyl (TEMPOL) and diphenyleneiodium chloride (DPI) were used. mRNA expression of ET-1, ETA receptor, ETB receptor, and fibronectin (FN) was analyzed by real-time polymerase chain reaction (real-time PCR). The protein levels for FN and ET-1 were measured by ELISA. CM-H2DCFDA-sensitive reactive oxygen species (ROS) were evaluated by flow cytometry.

{diamondsuit} Results: D-Glucose significantly induced mRNA expression of ET-1 and the ETB receptor but not the ETA receptor. FN production under high glucose conditions was inhibited by BQ-788. ET-1 directly stimulated HPMC to increase mRNA expression of FN and CM-H2DCFDA-sensitive ROS production. BQ-788, TEMPOL, and DPI inhibited mRNA expression of FN induced by ET-1.

{diamondsuit} Conclusion: The present study suggests that high-glucose-induced FN synthesis is mediated by the ET-1/ETB receptor pathway and, therefore, an ETB receptor antagonist may be useful in preventing FN production in HPMC.

KEY WORDS: Endothelin; endothelin receptor antagonist; fibronectin; high glucose; human peritoneal mesothelial cell; peritoneal fibrosis; reactive oxygen species.

Received 15 July 2005; accepted 30 September 2005.






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