Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway

Abstract

Background An enhanced renin‐angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease‐activated receptors (PAR). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren‐TG). Methods and Results The 12‐ to 16‐week‐old Ren‐TG and wild‐type mice were orally administered with or without 6 or 12 mg/kg of rivaroxaban for 1 or 4 months. Plasma factor Xa was significantly increased in the Ren‐TG compared with the wild‐type mice and was reduced by 12 mg/kg of rivaroxaban (P<0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8‐month‐old Ren‐TG than in the wild‐type mice (69.6±29 versus 20.1±8.2 μg/day; P<0.01). Treatment with 12 mg/kg of rivaroxaban for 4 months decreased the UAE to 38.1±13.2 μg/day (P<0.01). Moreover, rivaroxaban treatment attenuated histologic changes of glomerular hypertrophy, mesangial matrix expansion, effacement of the podocyte foot process, and thickened glomerular basement membrane in the Ren‐TG. The renal expression of PAR‐2 was increased in the Ren‐TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of PAR‐2 and inflammatory genes and nuclear factor–‐κB activation were induced by angiotensin II stimulation, but were inhibited by rivaroxaban. PAR‐2 knockdown by small interfering RNA also attenuated the PAR‐2‐related inflammatory gene expressions. Conclusions These findings indicate that rivaroxaban exerts protective effects against angiotensin II–induced renal damage, partly through inhibition of the PAR‐2 signaling‐mediated inflammatory response.

Keywords

• albuminuria
• podocytes
• protease‐activated receptor‐2
• renin‐angiotensin system
• rivaroxaban