PS-B08-3: DILATED CARDIOMYOPATHY MOUSE MODEL AGGRAVATES ACUTE KIDNEY INJURY

Abstract

Objective: The relation between cardiac and renal diseases is well known, and the concept of the cardio-renal syndrome has attracted much attention in recent years. However, the molecular mechanism of the cardio-renal syndrome is still unclear. In this study, we used αMHC-dominant negative Neuron-Restrictive Silencer Factor (NRSF) transgenic mice (Tg mice), a mouse model of dilated cardiomyopathy with gradually worsening ejection fraction, to elucidate the pathogenesis of acute kidney injury in the setting of chronic heart failure. Design and Methods: Sixteen-week-old Tg and wild-type mice were subjected to unilateral nephrectomy and 45-minute ischemia reperfusion injury (IRI) to the remaining kidney, and then the kidneys and hearts were retrieved 72 hours later. The control group were subjected to unilateral nephrectomy without IRI. Results: Heart weights were significantly heavier in Tg mice in both control and IRI-treated groups. In the control group, serum creatinine and blood urea nitrogen were unchanged between wild-type and Tg mice. However, serum creatinine and blood urea nitrogen were significantly elevated in Tg mice compared to wild-type mice in the IRI-treated group, and only IRI-treated Tg mice died within 72 hours after IRI (6/14). Furthermore, mRNA expression of Ccl2 and Lcn2 (NGAL) in the whole kidney was significantly elevated in IRI-treated wild-type mice, and was more upregulated in Tg mice. Periodic acid-Schiff staining showed that tubular injuries, such as dilation of tubules, cast formation and tubular atrophy, were exacerbated in IRI-treated Tg mice. In microarray analysis of IRI-treated kidneys from wild-type and Tg mice, several candidate genes were upregulated in Tg mice. Conclusions: In dilated cardiomyopathy model mouse, inflammation and histological changes were aggravated after IRI, suggesting that chronic heart failure augments renal impairment in acute kidney injury.