Tamoxifen downregulates connective tissue growth factor to ameliorate peritoneal fibrosis.
Peritoneal fibrosis (PF), including simple sclerosis and encapsulating peritoneal sclerosis (EPS), is a serious complication in patients on long-term peritoneal dialysis. Tamoxifen has successfully been used in treating EPS; however, the mechanism of tamoxifen in treating EPS fibrosis disorders remains unclear. This study demonstrates a possible antifibrotic mechanism of tamoxifen. A bleach-induced PF rat model was applied as the in vivo treatment target. Tamoxifen was intraperitoneally injected daily to treat PF. The PF scores and thickness of the submesothelial zone over the liver surface were measured as indicators for the severity of PF. Human peritoneal mesothelial cells (HPMC) were used as an in vitro model to test the antifibrotic effect of tamoxifen. Gene expressions of transforming growth factors-β (TGF-β), connective tissue growth factor (CTGF) and collagen were investigated using quantitative polymerase chain reactions. In HPMC, tamoxifen showed paradoxical effects between collagen I and TGF-β. Tamoxifen also inhibited TGF-β-induced collagen and CTGF. The possible antifibrotic effect of tamoxifen is through inhibiting CTGF to block collagen synthesis, although it enhances TGF-β which increases fibrosis. These results provide a possible molecular mechanism for tamoxifen.
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan, ROC.
Jenq-Wen
JW
Huang
Chung-Jen
CJ
Yen
Hon-Yen
HY
Wu
Chih-Kang
CK
Chiang
Hui-Teng
HT
Cheng
Yu-Chung
YC
Lien
Kuan-Yu
KY
Hung
Tun-Jun
TJ
Tsai
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism*; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D056627:Peritoneal Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012973:Sodium Hypochlorite / Q000009:adverse effects; D013629:Tamoxifen / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D024042:Collagen Type I; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D055513:Connective Tissue Growth Factor; D012973:Sodium Hypochlorite