{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:10:14Z","timestamp":1788419414766,"version":"build-2803163510"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,10,2]],"date-time":"2022-10-02T00:00:00Z","timestamp":1664668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81900668"],"award-info":[{"award-number":["81900668"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006400","name":"Alnylam Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006400","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>To address this, TGR (mRen2)27 rats (angiotensin II\u2010dependent hypertension model) were made diabetic with streptozotocin over 18\u2009weeks and treated with either vehicle, angiotensinogen siRNA, the AT<jats:sub>1<\/jats:sub> antagonist valsartan, the ACE inhibitor captopril, valsartan\u2009+\u2009siRNA or valsartan\u2009+\u2009captopril for the final 3\u00a0weeks. Mean arterial pressure (MAP) was measured via radiotelemetry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>MAP before treatment was 153\u2009\u00b1\u20092\u00a0mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA\u2009+\u2009valsartan. Treatment with siRNA lowered circulating angiotensinogen by &gt;99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver\u2010specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (&gt;95%) in the siRNA\u2009+\u2009valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Angiotensinogen siRNA exerts renoprotection in diabetic TGR (mRen2)27 rats and this relies, at least in part, on the suppression of renal angiotensin II formation from liver\u2010derived angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15955","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T09:38:41Z","timestamp":1663234721000},"page":"80-93","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Blood pressure\u2010independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes"],"prefix":"10.1111","volume":"180","author":[{"given":"Edwyn O.","family":"Cruz\u2010L\u00f3pez","sequence":"first","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC  Rotterdam The Netherlands"},{"name":"Department of Pharmacy Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estrellita","family":"Uijl","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC  Rotterdam The Netherlands"},{"name":"Division of Nephrology and Transplantation, Department of Internal Medicine Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian C.","family":"Clahsen\u2010van Groningen","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus MC  Rotterdam The Netherlands"},{"name":"Institute of Experimental Medicine and Systems Biology University Hospital Aachen, RWTH Aachen University  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"van Veghel","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Garrelds","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Domenig","sequence":"additional","affiliation":[{"name":"Attoquant Diagnostics  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Poglitsch","sequence":"additional","affiliation":[{"name":"Attoquant Diagnostics  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Zlatev","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Rooney","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Kasper","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Nioi","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don","family":"Foster","sequence":"additional","affiliation":[{"name":"Alnylam Pharmaceuticals  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5052-3585","authenticated-orcid":false,"given":"A. 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