Abstract
The aim of the present study was to perform kidney messenger ribonucleic acid (mRNA) analysis in normotensive, Hannover Sprague–Dawley (HanSD) rats and hypertensive, Ren-2 renin transgenic rats (TGR) after doxorubicin-induced heart failure (HF) with specific focus on genes that are implicated in the pathophysiology of HF-associated cardiorenal syndrome. We found that in both strains renin and angiotensin-converting enzyme mRNA expressions were upregulated indicating that the vasoconstrictor axis of the renin–angiotensin system was activated. We found that pre-proendothelin-1, endothelin-converting enzyme type 1 and endothelin type A receptor mRNA expressions were upregulated in HanSD rats, but not in TGR, suggesting the activation of endothelin system in HanSD rats, but not in TGR. We found that mRNA expression of cytochrome P-450 subfamily 2C23 was downregulated in TGR and not in HanSD rats, suggesting the deficiency in the intrarenal cytochrome P450-dependent pathway of arachidonic acid metabolism in TGR. These results should be the basis for future studies evaluating the pathophysiology of cardiorenal syndrome secondary to chemotherapy-induced HF in order to potentially develop new therapeutic approaches.
Highlights
Heart failure (HF) has become a major public health problem, in developed countries, affecting currently more than 6.5 million people in the United States of America and 9.2 million people in the European Union
[33] to gain a better insight into the possible role of potential compensatory activation of systemic and intrarenal neurohormonal systems, plasma and kidney concentrations of catecholamines, angiotensin II (ANG II), and angiotensin 1-7 (ANG 1-7) were determined. In this in vivo study, we found that two weeks after cessation of DOX administration [DOX was given in cumulative dose of 15 mg/kg body weight (BW) in six intraperitoneal (i.p.) injections over two weeks, which is a standard approach for introducing DOX-induced cardiomyopathy] [27,34], the transgenic rats (TGR) as well as control Hannover Sprague–Dawley (HanSD)
In order to confirm that the obtained kidney messenger ribonucleic acid (mRNA) expressions represent changes related to HF- associated cardiorenal syndrome, we evaluated the effects of DOX on cardiac weights and on the left ventricle (LV) mRNA expression of biomarkers that are recognized to be changed in HF [37,38,39]
Summary
Heart failure (HF) has become a major public health problem, in developed countries, affecting currently more than 6.5 million people in the United States of America and 9.2 million people in the European Union. There is an urgent need for new treatment strategies, which require a better understanding of the pathophysiological mechanism(s) underlying the progression of HF This can be achieved using small animal models, despite some apparent limitations [9,10]. The application of the MI model first enabled the demonstration that angiotensin-converting enzyme inhibitors (ACEi) attenuate HF and improve the long-term survival rate after the infarction [14,15] This has been confirmed in clinical studies [16,17], and ACEi has been established as the cornerstone therapy for HF [1,4,5,6,7]
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