TY - JOUR
T1 - Renoprotective effects of a factor Xa inhibitor
T2 - Fusion of basic research and a database analysis
AU - Horinouchi, Yuya
AU - Ikeda, Yasumasa
AU - Fukushima, Keijo
AU - Imanishi, Masaki
AU - Hamano, Hirofumi
AU - Izawa-Ishizawa, Yuki
AU - Zamami, Yoshito
AU - Takechi, Kenshi
AU - Miyamoto, Licht
AU - Fujino, Hiromichi
AU - Ishizawa, Keisuke
AU - Tsuchiya, Koichiro
AU - Tamaki, Toshiaki
N1 - Funding Information:
We appreciate the excellent technical support provided by the Support Center for Advanced Medical Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School. We would like to thank Editage (www. editage.jp) for English language editing. This work was supported partially by JSPS KAKENHI Grant (No. 16K16603 to Y.H.).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Renal tubulointerstitial injury, an inflammation-associated condition, is a major cause of chronic kidney disease (CKD). Levels of activated factor X (FXa), a blood coagulation factor, are increased in various inflammatory diseases. Therefore, we investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor (PAR)-1 and PAR-2 were significantly higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis and extracellular matrix expression were suppressed in UUO mice treated with the FXa inhibitor edoxaban. Additionally, edoxaban attenuated UUO-induced macrophage infiltration and inflammatory molecule upregulation. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against CKD by inhibiting tubulointerstitial fibrosis.
AB - Renal tubulointerstitial injury, an inflammation-associated condition, is a major cause of chronic kidney disease (CKD). Levels of activated factor X (FXa), a blood coagulation factor, are increased in various inflammatory diseases. Therefore, we investigated the protective effects of an FXa inhibitor against renal tubulointerstitial injury using unilateral ureteral obstruction (UUO) mice (a renal tubulointerstitial fibrosis model) and the Food and Drug Administration Adverse Events Reporting System (FAERS) database. The renal expression levels of FX and the FXa receptors protease-activated receptor (PAR)-1 and PAR-2 were significantly higher in UUO mice than in sham-operated mice. UUO-induced tubulointerstitial fibrosis and extracellular matrix expression were suppressed in UUO mice treated with the FXa inhibitor edoxaban. Additionally, edoxaban attenuated UUO-induced macrophage infiltration and inflammatory molecule upregulation. In an analysis of the FAERS database, there were significantly fewer reports of tubulointerstitial nephritis for patients treated with FXa inhibitors than for patients not treated with inhibitors. These results suggest that FXa inhibitors exert protective effects against CKD by inhibiting tubulointerstitial fibrosis.
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U2 - 10.1038/s41598-018-29008-2
DO - 10.1038/s41598-018-29008-2
M3 - Article
C2 - 30022146
AN - SCOPUS:85050353197
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 10858
ER -