title: Impaired post-infarction cardiac remodeling in chronic kidney disease is due to excessive renin release.
abstract: The complex pathophysiological interactions between heart and kidney diseases are collectively known as cardiorenal syndrome. The renin-angiotensin system (RAS) may have a pivotal role in the development of cardiorenal syndrome. The aim of this study was to elucidate the RAS activity responsible for adverse post-infarction remodeling and prognosis in mice with renal failure. To establish the type IV cardiorenal syndrome model, 5/6 nephrectomy (NTX) was performed in a surgical procedure, followed by the induction of myocardial ischemia (MI) by a coronary artery ligation 4 weeks later. NTX and MI resulted in deteriorated left ventricular remodeling and RAS activation, which was improved by an aliskiren that appeared to be independent of renal function and blood pressure (BP). Moreover, MI induced in renin and angiotensinogen double-transgenic (Tg) mice showed comparable effects to MI plus NTX mice, including advanced ventricular remodeling and enhancement of RAS, oxidative stress, and monocytes chemoattractant protein (MCP)-1. Aliskiren suppressed these changes in the MI-induced Tg mice. In in vitro study, Nox2 expression was elevated by the stimulation of plasma from NTX mice in isolated neonatal cardiomyocytes. However, Nox2 upregulation was negated when we administered plasma from aliskiren-treated-NTX mice or isolated cardiomyocytes from AT1-deficient mice. Primary mononuclear cells also showed an upregulation in the expression of Nox2 and MCP-1 by stimulation with plasma from NTX mice. Our data suggest that renal disorder results in ventricular dysfunction and deteriorates remodeling after MI through excessive RAS activation. Moreover, renin inhibition improved the changes caused by cardiorenal syndrome.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogawa
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takayama
authors.forename: Takaaki
authors.initials: T
authors.lastname: Senbonmatsu
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005650:Fumarates / Q000494:pharmacology; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D009392:Nephrectomy; D018384:Oxidative Stress / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D000577:Amides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005650:Fumarates; C446481:aliskiren; D009320:Atrial Natriuretic Factor; D012083:Renin