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. It is well known that there is a complex relationship between cardiovascular and renal diseases. In fact, end-stage renal disease or decreased estimated glomerular filtration rate correlates with an increased risk of cardiovascular diseases. 1 This clinical condition is known as cardiorenal syndrome. In addition, the presence of chronic kidney disease (CKD) is a relatively frequent complication in patients with advanced heart failure and left ventricular (LV) dysfunction. Its presence is associated with a worse prognosis following cardiovascular diseases. 2 Although preventing this condition includes identification and amelioration of the precipitating factors and connections, 3 the pathophysiological mechanisms of the syndrome remain to be elucidated. It is also known that the presence of CKD increases severity, worsens the response to treatment, and is associated with poor cardiac and renal outcomes in cardiorenal syndrome. 4,5 The renin-angiotensin system (RAS) has a critical role in the development of cardiovascular and renal disease in a clinical setting. It has been reported that the role of RAS in congestive heart failure (CHF) and CKD is complex owing to involvement of multiple peptides and receptors. Increased RAS activity results in the development of CHF by stimulation of cardiac hypertrophy, apopt...

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“…In addition, LV ejection fraction (EF) value, fractional shortening (FS), and LV mass were calculated, as previously described [19]. All measurements were repeated thrice from at least 10 consecutive cardiac cycles, and were analyzed by a single observer blinded to the treatment protocol, according to the recommendations of the American Society of Echocardiography [17, 20]. The mean values were used for data analysis.…”

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“…Real-time PCR in a Step One real-time PCR system (Applied Biosystems) was used to determine the mRNA expression of IFN-␥ (Assay ID: Rn99999014_m1), IL-2 (Assay ID: Rn00587673_m1), and MCP-1 (Assay ID: Rn00580555_m1) and 18s rRNA (Assay ID: Hs99999901_s1) as a control. cDNA was run in duplicates, quantitative data were calculated using the comparative CT (⌬⌬CT) method, and the mRNA expression was normalized by normal rat hearts (28,32).…”