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.

Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models

“…Similarly, RVX dampened the expression of VCAM-1, ICAM-1, MCP-1, IL-8, CXCL1, CXCL2, TF in thrombin stimulated human endothelial cells [ 19 ], as well as IL-6, IL-1β, TNF-α, MMP9, and COL-1 expression in hypoxic cardiac myocytes and fibroblasts [ 23 ]. Similarly, also TNF-α, MCP-1, IL-6 expression in angiotensin II-induced inflammatory response in human podocytes was modulated by RVX [ 24 ].…”

“…Also, hypertensive renal damage resulted to be ameliorated by RVX chronic pre-treatment of renin overexpressing mice via specifically targeting of TNF-α, MCP-1, and IL-6 [ 24 ]. Thus paving the way also to the other newer FXa inhibitor, which recently demonstrated to affect VCAM-1 and ICAM-1 in uremia induced vascular dysfunction [ 65 ].…”

“…We now translate these findings in vivo by showing an improvement of vascular tone in endotoxin-induced hypotension and proinflammatory response following RVX pre-treatment. The effect could rely on the control of FXa-PAR-2 [ 47 – 49 , 69 , 76 ] and TL-4 /NF-κB signaling [ 24 , 50 , 51 , 77 ].…”

“…In addition to this, experimental studies proposed a series of vascular protective properties of NOAC via inhibition of FXa [ 14 – 26 ]. These include potential anti-inflammatory effects [ 15 , 19 – 21 , 23 , 24 , 27 ], that might perhaps impact vascular function and pathology [ 14 , 25 ]. Indeed inflammation is one of the main contributing factors in coronary artery disease leading to the development of atherosclerosis [ 28 ].…”

“…Clinical studies with NOACS have shown that these drugs reduce the incidence of cardiovascular events including coronary and peripheral artery disease, cerebral ischemia, thrombosis, thromboembolic events, and atherosclerosis [12,13]. In addition to this, experimental studies proposed a series of vascular protective properties of NOAC via inhibition of FXa [14][15][16][17][18][19][20][21][22][23][24][25][26]. These include potential anti-inflammatory effects [15,[19][20][21]23,24,27], that might perhaps impact vascular function and pathology [14,25].…”