Renoprotective effects of a factor Xa inhibitor: fusion of basic research and a database analysis

Abstract

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.

Protease‐activated receptor‐1 contributes to renal injury and interstitial fibrosis during chronic obstructive nephropathy

“…We first assessed PAR‐1 expression levels in control (contralateral) and obstructed kidney sections of wild‐type mice. As shown in Figure A, PAR‐1 expression is low in non‐obstructed kidneys and significantly increases 7 and 10 days after the induction of UUO (which is in line with a recent study showing PAR‐1 induction after UUO using immunohistochemistry). As expected, no PAR‐1 mRNA was measured in the PAR‐1‐deficient mice during the experiment (Figure A).…”

“…The identification of the endogenous PAR‐1 agonist in the setting of UUO‐induced renal fibrosis is therefore a major challenge. Interestingly, however, during preparation of our manuscript, it was shown that UUO‐induced renal damage and tubulointerstitial fibrosis was suppressed in UUO mice treated with the specific FXa inhibitor edoxaban . Although this may pinpoint FXa as the endogenous PAR‐1 agonist driving PAR‐1‐dependent renal injury during UUO, it was not shown that the effect of FX inhibition was PAR‐1 dependent.…”

“…*P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001 (one-way ANOVA followed by Bonferroni multiple comparisons test) was suppressed in UUO mice treated with the specific FXa inhibitor edoxaban. 23 Although this may pinpoint FXa as the endogenous PAR-1 agonist driving PAR-1-dependent renal injury during UUO, it was not shown that the effect of FX inhibition was PAR-1 dependent.…”

The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis

“…Beneficial effects of vorapaxar not only apply to the maladaptive repair process in tubular cells, but also to the endothelial compartment during the development and progression of CKD. A recent study also showed a beneficial effect of direct FXa inhibition with edoxaban on fibrotic changes in UUO model [65]. Edoxaban is mainly eliminated via the kidneys and is contraindicated in advanced CKD [66], whereas vorapaxar is mainly eliminated through feces Downloaded from http://portlandpress.com/clinsci/article-pdf/doi/10.1042/CS20200923/895377/cs-2020-0923.pdf by guest on 01 November 2020 (58%), with only 25% renal excretion [67].…”

Edoxaban Exerts Antioxidant Effects Through FXa Inhibition and Direct Radical-Scavenging Activity

“…Notably, PAR2 has been reported to be closely associated with inflammation [6,7]. Interestingly, it has been reported that renal FX and PAR2 mRNA and urinary FXa activity are increased, although there is no change in the activity of plasma FXa in mouse models of diabetic nephropathy [8] and unilateral ureteral ligation renal interstitial fibrosis [9]. Moreover, edoxaban, an FXa inhibitor, reportedly ameliorates kidney disease by suppressing not only inflammation but also renal fibrosis in the two aforementioned mouse models.…”