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We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rats were subjected to subtotal nephrectomy followed 9\u00a0weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">kB<\/jats:styled-content> inhibitor <jats:styled-content style=\"fixed-case\">PDTC<\/jats:styled-content>, the <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and <jats:styled-content style=\"fixed-case\">CTGF<\/jats:styled-content> gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (<jats:styled-content style=\"fixed-case\">MAP<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content> type 1 (<jats:styled-content style=\"fixed-case\">AT<\/jats:styled-content>1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five\u2010drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.12829","type":"journal-article","created":{"date-parts":[[2016,11,7]],"date-time":"2016-11-07T16:41:24Z","timestamp":1478536884000},"page":"382-393","source":"Crossref","is-referenced-by-count":12,"title":["Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation"],"prefix":"10.1111","volume":"220","author":[{"given":"N. R.","family":"Oosterhuis","sequence":"first","affiliation":[{"name":"Department of Nephrology and Hypertension University Medical Center Utrecht Utrecht the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L. 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