{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:07:07Z","timestamp":1785434827902,"version":"3.56.0"},"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001563","name":"Otago Medical Research Foundation","doi-asserted-by":"publisher","award":["Laurensen Award"],"award-info":[{"award-number":["Laurensen Award"]}],"id":[{"id":"10.13039\/501100001563","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009477","name":"Lottery Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009477","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Healthcare Otago Charitable Trust"},{"DOI":"10.13039\/501100001518","name":"Maurice and Phyllis Paykel Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001518","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Aims<\/jats:title>\n<jats:p>The renin-angiotensin-aldosterone axis plays a key role in mediating cardiac and kidney injury. Mineralocorticoid receptor antagonism has beneficial effects on cardiac dysfunction, but effects are less well quantified in the cardiorenal syndrome. This study investigated cardiac and kidney pathophysiology following permanent surgical ligation to induce myocardial infarction (MI) in hypertensive animals with or without mineralocorticoid receptor antagonism.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Hypertension was induced in adult male Cyp1a1Ren2 rats. Hypertensive animals underwent MI surgery (n = 6), and were then treated daily with spironolactone for 28 days with serial systolic blood pressure measurements, echocardiograms and collection of urine and serum biochemical data. They were compared to hypertensive animals (n = 4), hypertensive animals treated with spironolactone (n = 4), and hypertensive plus MI without spironolactone (n = 6). Cardiac and kidney tissue was examined for histological and immunohistochemical analysis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>MI superimposed on hypertension resulted in an increase in interstitial cardiac fibrosis (p&lt;0.001), renal cortical interstitial fibrosis (p&lt;0.01) and glomerulosclerosis (p&lt;0.01). Increased fibrosis was accompanied by myofibroblast and macrophage infiltration in the heart and the kidney. Spironolactone post-MI, diminished the progressive fibrosis (p&lt;0.001) and inflammation (myofibroblasts (p&lt;0.05); macrophages (p&lt;0.01)) in both the heart and the kidney, despite persistently elevated SBP (182\u00b119 mmHg). Despite the reduction in inflammation and fibrosis, spironolactone did not modify ejection fraction, proteinuria, or renal function when compared to untreated animals post MI.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>This model of progressive cardiorenal dysfunction more closely replicates the clinical setting. Mineralocorticoid receptor blockade at a clinically relevant dose, blunted progression of cardiac and kidney fibrosis with reduction in cardiac and kidney inflammatory myofibroblast and macrophage infiltration. Further studies are underway to investigate the combined actions of angiotensin blockade with mineralocorticoid receptor blockade.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0260554","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T18:28:10Z","timestamp":1638210490000},"page":"e0260554","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["The effect of spironolactone on cardiac and renal fibrosis following myocardial infarction in established hypertension in the transgenic Cyp1a1Ren2 rat"],"prefix":"10.1371","volume":"16","author":[{"given":"C. J.","family":"Leader","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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Valero-Mu\u00f1oz","year":"2017","journal-title":"J Am Collage Cardiol Basic to Transl Sci"},{"issue":"2","key":"pone.0260554.ref004","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1136\/hrt.2004.042473","article-title":"Left ventricular hypertrophy in hypertension: Its arrhythmogenic potential","volume":"91","author":"T Kahan","year":"2005","journal-title":"Heart"},{"issue":"2","key":"pone.0260554.ref005","doi-asserted-by":"crossref","first-page":"41","DOI":"10.5494\/wjh.v5.i2.41","article-title":"Hypertensive cardiomyopathy: A clinical approach and literature review","volume":"5","author":"K Kuroda","year":"2015","journal-title":"World J Hypertens"},{"issue":"3","key":"pone.0260554.ref006","first-page":"e28","article-title":"Heart Disease and Stroke Statistics\u20142014 Update: A Report From the American Heart Association","volume":"129","author":"AS Go","year":"2014","journal-title":"Circulation"},{"issue":"10","key":"pone.0260554.ref007","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1161\/CIR.0000000000000485","article-title":"Heart Disease and Stroke Statistics\u20142017 Update: A Report From the American Heart Association","volume":"135","author":"EJ Benjamin","year":"2017","journal-title":"Circulation"},{"issue":"5","key":"pone.0260554.ref008","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1007\/s00134-008-1017-8","article-title":"Cardiorenal syndrome: Refining the definition of a complex symbiosis gone wrong","volume":"34","author":"C Ronco","year":"2008","journal-title":"Intensive Care Med"},{"issue":"2","key":"pone.0260554.ref009","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s10741-010-9224-0","article-title":"Cardio-renal syndromes: A systematic approach for consensus definition and classification","volume":"17","author":"C Ronco","year":"2012","journal-title":"Heart Fail 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Napoli","year":"2011","journal-title":"Future Cardiol"},{"issue":"6","key":"pone.0260554.ref014","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1038\/ki.1987.156","article-title":"Renal and circulatory mechanisms in congestive heart failure","volume":"31","author":"VJ Dzau","year":"1987","journal-title":"Kidney Int"},{"issue":"10","key":"pone.0260554.ref015","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nrneph.2016.113","article-title":"Heart failure and kidney dysfunction: Epidemiology, mechanisms and management","volume":"12","author":"JC Schefold","year":"2016","journal-title":"Nat Rev Nephrol."},{"issue":"2","key":"pone.0260554.ref016","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ahj.2004.08.005","article-title":"Characteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National 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myocardial fibrosis in systemic arterial hypertension","volume":"71","author":"CG Brilla","year":"1993","journal-title":"Am J Cardiol"},{"issue":"2","key":"pone.0260554.ref020","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/S0735-1097(00)01129-3","article-title":"Prevention of aortic and cardiac fibrosis by spironolactone in old normotensive rats","volume":"37","author":"P Lacolley","year":"2001","journal-title":"J Am Coll Cardiol"},{"issue":"5","key":"pone.0260554.ref021","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/jce.12379","article-title":"Eplerenone-Mediated Regression of Electrical Activation Delays and Myocardial Fibrosis in Heart Failure","volume":"25","author":"C Tanaka-Esposito","year":"2014","journal-title":"J Cardiovasc Electrophysiol"},{"key":"pone.0260554.ref022","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/S1734-1140(11)70613-2","article-title":"Long-term use of low-dose spironolactone in spontaneously hypertensive 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Colussi","year":"2012","journal-title":"J Hypertens"},{"key":"pone.0260554.ref029","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/ki.2012.352","article-title":"Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury","volume":"83","author":"J Barrera-Chimal","year":"2012","journal-title":"Kidney Int"},{"issue":"5","key":"pone.0260554.ref030","doi-asserted-by":"crossref","first-page":"F923","DOI":"10.1152\/ajprenal.00015.2002","article-title":"Sodium transporter abundance profiling in kidney: effect of spironolactone","volume":"283","author":"J Nielsen","year":"2002","journal-title":"Am J Physiol Renal Physiol"},{"issue":"1","key":"pone.0260554.ref031","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/sj.ki.5000438","article-title":"Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats","volume":"70","author":"KH Han","year":"2006","journal-title":"Kidney Int"},{"issue":"5","key":"pone.0260554.ref032","doi-asserted-by":"crossref","first-page":"F1584","DOI":"10.1152\/ajprenal.00124.2007","article-title":"Aldosterone receptor antagonism alleviates proteinuria, but not malignant hypertension, in Cyp1a1-Ren2 transgenic rats","volume":"293","author":"RM Ortiz","year":"2007","journal-title":"Am J Physiol Renal Physiol"},{"issue":"4","key":"pone.0260554.ref033","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1161\/01.RES.44.4.503","article-title":"Myocardial infarct size and ventricular function in rats","volume":"44","author":"M a Pfeffer","year":"1979","journal-title":"Circ Res"},{"issue":"11","key":"pone.0260554.ref034","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/0022-2828(90)90060-F","article-title":"Changes in heart function and cardiac cell size in rats with chronic myocardial infarction","volume":"22","author":"HG Zimmer","year":"1990","journal-title":"J Mol Cell Cardiol"},{"key":"pone.0260554.ref035","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1006\/jmcc.1994.1140","article-title":"Mechanical abnormalities in the rat ischemic heart failure model which lie downstream to cAMP production","volume":"26","author":"TP Stuver","year":"1994","journal-title":"J Mol Cell Cardiol"},{"issue":"1","key":"pone.0260554.ref036","first-page":"8","article-title":"Effects of alatriopril, a mixed inhibitor of atriopeptidase and angiotensin I-converting enzyme, on cardiac hypertrophy and hormonal responses in rats with myocardial infarction. Comparison with captopril","volume":"270","author":"J Bralet","year":"1994","journal-title":"J Pharmacol Exp Ther"},{"issue":"3","key":"pone.0260554.ref037","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1016\/j.ijcard.2012.12.065","article-title":"Subtotal nephrectomy accelerates pathological cardiac remodeling post-myocardial infarction: Implications for cardiorenal syndrome","volume":"168","author":"S Liu","year":"2013","journal-title":"Int J Cardiol"},{"key":"pone.0260554.ref038","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1093\/ndt\/gfn233","article-title":"Myocardial infarction does not further impair renal damage in 5\/6 nephrectomized rats","volume":"23","author":"WAKM Windt","year":"2008","journal-title":"Nephrol Dial Transplant"},{"key":"pone.0260554.ref039","doi-asserted-by":"crossref","first-page":"H845","DOI":"10.1152\/ajpheart.00261.2011","article-title":"Subtotal nephrectomy plus coronary ligation leads to more pronounced damage in both organs than either nephrectomy or coronary ligation","volume":"302","author":"LG Bongartz","year":"2012","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"9","key":"pone.0260554.ref040","doi-asserted-by":"crossref","first-page":"F1253","DOI":"10.1152\/ajprenal.00392.2012","article-title":"Target organ cross talk in cardiorenal syndrome: animal models","volume":"303","author":"LG Bongartz","year":"2012","journal-title":"Am J Physiol Renal Physiol"},{"key":"pone.0260554.ref041","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s10741-011-9279-6","article-title":"Animal models of cardiorenal syndrome: a review","volume":"17","author":"MK Szymanski","year":"2012","journal-title":"Heart Fail Rev"},{"key":"pone.0260554.ref042","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fphar.2017.00313","article-title":"Mineralocorticoid receptor signaling as a therapeutic target for renal and cardiac fibrosis","volume":"8","author":"GH Tesch","year":"2017","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0260554.ref043","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/10739680490266207","article-title":"Enhancement of glucocorticoid and mineralocorticoid receptor density in the microcirculation of the spontaneously hypertensive rat","volume":"11","author":"FA Delano","year":"2004","journal-title":"Microcirculation"},{"issue":"3","key":"pone.0260554.ref044","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1161\/HYPERTENSIONAHA.109.131110","article-title":"Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone\/salt-induced cardiac fibrosis and increased blood pressure","volume":"54","author":"AJ Rickard","year":"2009","journal-title":"Hypertension"},{"key":"pone.0260554.ref045","doi-asserted-by":"crossref","first-page":"3350","DOI":"10.1172\/JCI41080","article-title":"Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice","volume":"120","author":"MG Usher","year":"2010","journal-title":"J Clin Invest"},{"issue":"4","key":"pone.0260554.ref046","doi-asserted-by":"crossref","first-page":"e36311","DOI":"10.1371\/journal.pone.0036311","article-title":"Activation of thiazide-sensitive co-transport by angiotensin II in the cyp1a1-Ren2 hypertensive rat","volume":"7","author":"A Ashek","year":"2012","journal-title":"PLoS One"},{"issue":"12","key":"pone.0260554.ref047","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1097\/HJH.0b013e3282ef84f8","article-title":"Transient prehypertensive treatment in spontaneously hypertensive rats: A comparison of spironolactone and losartan regarding long-term blood pressure and target organ damage","volume":"25","author":"M Baumann","year":"2007","journal-title":"J Hypertens"},{"issue":"11","key":"pone.0260554.ref048","doi-asserted-by":"crossref","first-page":"3456","DOI":"10.1093\/ndt\/gfn301","article-title":"Blood pressure versus direct mineralocorticoid effects on kidney inflammation and fibrosis in DOCA-salt hypertension","volume":"23","author":"B Klanke","year":"2008","journal-title":"Nephrol Dial Transplant"},{"issue":"7","key":"pone.0260554.ref049","doi-asserted-by":"crossref","first-page":"797","DOI":"10.3390\/ijms17070797","article-title":"Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension","volume":"17","author":"N Mu\u00f1oz-Durango","year":"2016","journal-title":"Int J Mol Sci"},{"issue":"3","key":"pone.0260554.ref050","doi-asserted-by":"crossref","first-page":"96","DOI":"10.3390\/biom8030096","article-title":"Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease","volume":"8","author":"S Gorini","year":"2018","journal-title":"Biomolecules"},{"issue":"2","key":"pone.0260554.ref051","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.kint.2019.02.030","article-title":"Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis","volume":"96","author":"J Barrera-Chimal","year":"2019","journal-title":"Kidney Int"},{"key":"pone.0260554.ref052","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1161\/01.HYP.0000255636.11931.a2","article-title":"Aldosterone and Renal Injury Podocyte as the Target for Aldosterone Roles of Oxidative Stress and Sgk1","volume":"49","author":"S Shibata","year":"2007","journal-title":"Hypertension"},{"issue":"1","key":"pone.0260554.ref053","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ejphar.2008.06.019","article-title":"Spironolactone exhibits direct renoprotective effects and inhibits renal renin\u2013angiotensin\u2013aldosterone system in diabetic rats","volume":"589","author":"M Taira","year":"2008","journal-title":"Eur J Pharmacol"},{"issue":"4","key":"pone.0260554.ref054","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1111\/j.1523-1755.2004.00913.x","article-title":"Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats","volume":"66","author":"G Fujisawa","year":"2004","journal-title":"Kidney Int"},{"issue":"3","key":"pone.0260554.ref055","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1152\/ajprenal.00197.2009","article-title":"Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats","volume":"297","author":"J Du","year":"2009","journal-title":"Am J Physiol\u2014Ren Physiol"},{"issue":"10","key":"pone.0260554.ref056","doi-asserted-by":"crossref","first-page":"e14448","DOI":"10.14814\/phy2.14448","article-title":"Spironolactone mitigates, but does not reverse, the progression of renal fibrosis in a transgenic 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[RALES]).","volume":"78","author":"The RALES investigators","year":"1996","journal-title":"Am J Cardiol"},{"issue":"14","key":"pone.0260554.ref066","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1056\/NEJMoa030207","article-title":"Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction","volume":"348","author":"B Pitt","year":"2003","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0260554.ref067","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1161\/CIRCHEARTFAILURE.113.000887","article-title":"Cardiac structure and function in heart failure with preserved ejection fraction: Baseline findings from the echocardiographic study of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial.","volume":"7","author":"AM Shah","year":"2014","journal-title":"Circ Hear 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