{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:51:46Z","timestamp":1790175106330,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2019,4,16]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              An enhanced renin\u2010angiotensin system causes hypertensive renal damage. Factor Xa not only functions in the coagulation cascade but also activates intracellular signaling through protease\u2010activated receptors (\n              <jats:styled-content style=\"fixed-case\">PAR<\/jats:styled-content>\n              ). We investigated the effects of rivaroxaban, a factor Xa inhibitor, on hypertensive renal damage in hypertensive mice overexpressing renin (Ren\u2010TG).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The 12\u2010 to 16\u2010week\u2010old Ren\u2010TG and wild\u2010type mice were orally administered with or without 6 or 12\u00a0mg\/kg of rivaroxaban for 1 or 4\u00a0months. Plasma factor Xa was significantly increased in the Ren\u2010TG compared with the wild\u2010type mice and was reduced by 12\u00a0mg\/kg of rivaroxaban (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05). Urinary albumin excretion (UAE) was higher in the nontreated 8\u2010month\u2010old Ren\u2010TG than in the wild\u2010type mice (69.6\u00b129 versus 20.1\u00b18.2\u00a0\u03bcg\/day;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.01). Treatment with 12\u00a0mg\/kg of rivaroxaban for 4\u00a0months decreased the\n              <jats:styled-content style=\"fixed-case\">UAE<\/jats:styled-content>\n              to 38.1\u00b113.2\u00a0\u03bcg\/day (\n              <jats:italic>P<\/jats:italic>\n              &lt;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\u2010TG. The renal expression of\n              <jats:styled-content style=\"fixed-case\">PAR<\/jats:styled-content>\n              \u20102 was increased in the Ren\u2010TG, but was inhibited with rivaroxaban treatment. In vitro study using the human podocytes showed that the expressions of\n              <jats:styled-content style=\"fixed-case\">PAR<\/jats:styled-content>\n              \u20102 and inflammatory genes and nuclear factor\u2013\u2010\u03baB activation were induced by angiotensin\n              <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\n              stimulation, but were inhibited by rivaroxaban.\n              <jats:styled-content style=\"fixed-case\">PAR<\/jats:styled-content>\n              \u20102 knockdown by small interfering\n              <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n              also attenuated the\n              <jats:styled-content style=\"fixed-case\">PAR<\/jats:styled-content>\n              \u20102\u2010related inflammatory gene expressions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              These findings indicate that rivaroxaban exerts protective effects against angiotensin II\u2013induced renal damage, partly through inhibition of the\n              <jats:styled-content style=\"fixed-case\">PAR<\/jats:styled-content>\n              \u20102 signaling\u2010mediated inflammatory response.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.119.012195","type":"journal-article","created":{"date-parts":[[2019,4,6]],"date-time":"2019-04-06T09:20:11Z","timestamp":1554542411000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":40,"title":["Rivaroxaban, a Direct Factor Xa Inhibitor, Ameliorates Hypertensive Renal Damage Through Inhibition of the Inflammatory Response Mediated by Protease\u2010Activated Receptor Pathway"],"prefix":"10.1161","volume":"8","author":[{"given":"Hiroaki","family":"Ichikawa","sequence":"first","affiliation":[{"name":"Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Narita","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuyo","family":"Narita","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Stroke and Cerebrovascular Medicine Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Osanai","sequence":"additional","affiliation":[{"name":"Department of Nursing Science Hirosaki University Graduate School of Health Sciences Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Okumura","sequence":"additional","affiliation":[{"name":"Division of Cardiology Saiseikai Kumamoto Hospital Kumamoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Tomita","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Nephrology Hirosaki University Graduate School of Medicine Hirosaki Japan"},{"name":"Department of Stroke and Cerebrovascular Medicine Hirosaki University Graduate School of Medicine Hirosaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.3317\/jraas.2000.036"},{"key":"e_1_3_2_3_2","first-page":"419","article-title":"Prothrombotic effects of angiotensin","volume":"45","author":"Brown NJ","year":"2000","unstructured":"Brown NJ, Vaughan DE. 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