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.

• Authors: Hiroaki Ichikawa, Michiko Shimada, Masato Narita, Ikuyo Narita, Yoshihiro Kimura, Makoto Tanaka, Tomohiro Osanai, Ken Okumura, Hirofumi Tomita
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 8 Issue 8 Pg. e012195 (04 16 2019) ISSN: 2047-9980 [Electronic] England
• PMID: 30957622 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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