P624Renal injury and increased paraventricular nuclear excitation consequent to chronic heart failure in a model of type 2 cardiorenal syndrome

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Abstract

Aims

Cardio-renal syndrome (CRS) is clinically recognised but poorly characterised. The primary aim of this study was to establish and characterise an animal model of de novo renal pathology arising secondary to cardiac insufficiency (type-2 CRS) in chronic heart failure. Neuronal excitation within the hypothalamic structures occurring following cardiac ischaemia can result in an increased sympathetic output to target organs such as the heart and kidney, and may acutely exacerbate heart failure (HF). In this study, the response to chronic heart failure was investigated at 90 days post-MI.

Methods

Using a Lewis rat model of ischaemic HF, we have established a model of type-2 CRS. Left ventricular (LV) infarction was induced by permanently occluding the left anterior descending (LAD) coronary artery and confirmed using cardiac troponin I levels. At 3 months post-ischaemic onset, renal clearance was assessed using 24hr urine and plasma creatinine and sodium collections taken immediately prior to termination. Cardiac haemodynamic function was assessed in the Langendorff mode at termination and kidneys isolated and processed for biochemical and histological analysis. The paraventricular hypothalamic nucleus was assessed using fluorescence microscopy for ROS levels and angiotensin type 1 receptor (AT1R) expression.

Results

All data were reported as sham vs. LAD occlusion groups with analysis conducted using a one tailed, unpaired t-test with Welch's correction. Animals were found to suffer an extensive LV infarct. LV weight was significantly increased following infarction and LV haemodynamic function (developed pressure and diastolic function) was severely compromised. Renal function assessed using CrCl was significantly decreased while FENa significantly increased. Renal (cortex and medulla) caspase 3/7 activity significantly increased in rats with cardiac infarcts. Histologically these kidneys showed evidence of glomerulosclerosis with basement membrane thickening and interstitial fibrosis. In the paraventricular nucleus, AT1R expression and ROS levels were significantly increased at 90 days following LAD ligation.

Conclusions

This is the first study to provide conclusive morphological, biochemical and functional evidence of renal damage in a rat model of HF representative of type-2 CRS. The presence of a paraventricular nuclear response to MI out to 90 days may represent a valuable pharmacological target in the future.

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