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

J Am Heart Assoc. 2019 Apr 16;8(8):e012195. doi: 10.1161/JAHA.119.012195.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / etiology
  • Albuminuria / metabolism*
  • Angiotensin II / pharmacology
  • Animals
  • Blood Coagulation / drug effects
  • Factor Xa Inhibitors / pharmacology*
  • Gene Knockdown Techniques
  • Glomerular Basement Membrane / drug effects
  • Glomerular Basement Membrane / pathology
  • Glomerular Mesangium / drug effects
  • Glomerular Mesangium / pathology
  • Humans
  • Hypertension / complications
  • Hypertension / metabolism*
  • In Vitro Techniques
  • Inflammation
  • Kidney Glomerulus / drug effects*
  • Kidney Glomerulus / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Podocytes / drug effects
  • Podocytes / metabolism
  • Podocytes / pathology
  • Receptor, PAR-2 / drug effects*
  • Receptor, PAR-2 / genetics
  • Receptor, PAR-2 / metabolism
  • Renal Insufficiency, Chronic / etiology
  • Renal Insufficiency, Chronic / metabolism
  • Renin / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rivaroxaban / pharmacology*
  • Vasoconstrictor Agents / pharmacology


  • F2RL1 protein, human
  • F2rl1 protein, mouse
  • Factor Xa Inhibitors
  • Receptor, PAR-2
  • Vasoconstrictor Agents
  • Angiotensin II
  • Rivaroxaban
  • Renin