Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway
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 hyper...
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| Format: | Article |
| Language: | English |
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Wiley
2019-04-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.119.012195 |
| _version_ | 1811332349597581312 |
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| author | Hiroaki Ichikawa Michiko Shimada Masato Narita Ikuyo Narita Yoshihiro Kimura Makoto Tanaka Tomohiro Osanai Ken Okumura Hirofumi Tomita |
| author_facet | Hiroaki Ichikawa Michiko Shimada Masato Narita Ikuyo Narita Yoshihiro Kimura Makoto Tanaka Tomohiro Osanai Ken Okumura Hirofumi Tomita |
| author_sort | Hiroaki Ichikawa |
| collection | DOAJ |
| description | 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. |
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| format | Article |
| id | doaj.art-765653b6c33b43ebab7c4410ab1c1b97 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T16:35:20Z |
| publishDate | 2019-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-765653b6c33b43ebab7c4410ab1c1b972022-12-22T02:39:27ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802019-04-018810.1161/JAHA.119.012195Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor PathwayHiroaki Ichikawa0Michiko Shimada1Masato Narita2Ikuyo Narita3Yoshihiro Kimura4Makoto Tanaka5Tomohiro Osanai6Ken Okumura7Hirofumi Tomita8Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki JapanDepartment of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki JapanDepartment of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki JapanDepartment of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki JapanDepartment of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki JapanDepartment of Stroke and Cerebrovascular Medicine Hirosaki University Graduate School of Medicine Hirosaki JapanDepartment of Nursing Science Hirosaki University Graduate School of Health Sciences Hirosaki JapanDivision of Cardiology Saiseikai Kumamoto Hospital Kumamoto JapanDepartment of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki JapanBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.119.012195albuminuriapodocytesprotease‐activated receptor‐2renin‐angiotensin systemrivaroxaban |
| spellingShingle | Hiroaki Ichikawa Michiko Shimada Masato Narita Ikuyo Narita Yoshihiro Kimura Makoto Tanaka Tomohiro Osanai Ken Okumura Hirofumi Tomita Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease albuminuria podocytes protease‐activated receptor‐2 renin‐angiotensin system rivaroxaban |
| title | Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway |
| title_full | Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway |
| title_fullStr | Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway |
| title_full_unstemmed | Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway |
| title_short | Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease‐Activated Receptor Pathway |
| title_sort | rivaroxaban a direct factor xa inhibitor ameliorates hypertensive renal damage through inhibition of the inflammatory response mediated by protease activated receptor pathway |
| topic | albuminuria podocytes protease‐activated receptor‐2 renin‐angiotensin system rivaroxaban |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.119.012195 |
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