The incidences of heart failure and renal failure has gradually increased. Renal insufficiency is an independent predictor of heart failure, while myocardial hypertrophy and heart function failure are serious complications of chronic renal failure, closely associated with mortality (12
). In this study, a rat model of CRS was established to examine the pathophysiological mechanism in order to identify effective drugs and early intervention therapy.
A successful model of CRS, not only simulates the clinical characteristics of CRS, including changes in the heart, kidney, hemodynamics and neuroendocrinology, but also evaluates the therapeutic effect. This model must include joint damages of kidney and heart, characterized by progressive deterioration of cardio-nephric function. The model must present systolic dysfunction confirmed by echocardiography and haemodynamics, resulting in decreased cardiac output. In addition, to further explore the latest clinical findings, increased enddiastolic pressure and venous congestion are also necessary conditions. At a histological level, the model must present characteristics of hypertrophy and fibrosis, particularly mismatched myocardial/capillary. To successfully represent kidney damage, the model must present characteristics of increased Cr and excretion of albumin, as well as decreased progressive renal function caused by a decrease in the glomerular filtration rate (GFR)/Cr clearance ratio. This study aimed to explore the physiopathological mechanism of a CRS model induced by three-quarters nephrectomy and subcutaneous injection of ISO.
Compared with previous models of simple heart or renal failure, rats in this study presented earlier renal and heart failure, characterized by significantly increased Cr, urine protein and left ventricular weight index, as well as decreased hemodynamic index, including ±dP/dtmax
and increased serum BNP. HE staining of the myocardium revealed clear hypertrophy of myocardial cells and myocardial fibrosis in the model group, indicating that reconstruction of myocardial hypertrophy had begun. Compared with heart failure caused only by ISO, the amount of subcutaneous injection of ISO was reduced in this model group. In the report of a CRS model by Van Dokkum et al
and Windt et al
), there was reduced interactive influence between heart and renal function. Dikow et al
) hypothesized that the increase in Cr aggravated the left ventricular remodeling of myocardial infarction. We consider that the differences in experimental design may be associated with the varying degrees of damage to the heart and kidney, as well as different induction times. We analyzed indices of heart and kidney function in this model and identified that serum BNP was positively correlated to Cr in the model group, with a correlation coefficient of 0.81 (P<0.01), which is consistent with the study by Butler et al
) and the retrospective study by Weinfeld et al
). The hemodynamic variable associated with worsening renal function was right atrial pressure. Heart and renal function may influence each other in the occurrence and development of diseases. This model simulates the process of heart failure complicated with renal failure.
The possible mechanisms of heart-kidney interactions that have previously been considered include hemodynamic changes, endothelial dysfunction, inflammation, activation of the renin-angiotensin aldosterone system (RAAS) and/or the sympathetic system, any of which may cause cascade reactions of other factors, leading to structural and functional damage to the heart and kidney (17
). The mechanism that causes and maintains heart-kidney interactions remains unclear. In this study, serum ALD and Ang II were significantly increased in the model group compared with the control group, indicating that activation of the RAAS is important in the occurrence of this model. At the same time, serum CRP was significantly increased in the model group compared with the control group (P<0.01), indicating that inflammation also plays a promoting role in this model of CRS. We also detected a marked change in urine protein, which is a strong and independent risk factor for cardiovascular disease. When it appears, proteinuria causes an accelerated atherosclerotic process, endothelial dysfunction, increased risk of terminal organ damage, serious cardiovascular events and mortality (19
). Rats in this model suffer heart-kidney interactions, then when CRS occurs, the prognosis becomes significantly worse.
Due to the physiological changes of decreased renal function caused by three-quarters nephrectomy, this model had an increased sensitivity to adverse factors in chronic heart failure. Inflammation and activation of the RAAS promotes the occurrence and development of cardiorenal failure. Hemodynamic changes cause an increase in Ang II release, vasoconstriction, contraction of the efferent glomerular arteriole, cardiac remodeling and an increase in aldosterone release, as well as water and sodium retention, which promote myocardial fibrosis (20
This study demonstrated that three-quarters nephrectomy complicated with subcutaneous injection of ISO induces concurrent heart and renal failure, with a high success rate, providing a simple, reliable and easy animal model for clinical discussion of the interactive mechanism of heart and renal function. However, this study did not investigate the development time of CRS, which is required to examine the illness and possible preventive therapeutic measures. This model is likely to be useful for further studies on the pathogenesis and development of heart-renal interaction at different stages.