Baumann, M; Leineweber, K; Tewiele, M; Wu, K; Türk, TR; Su, S; Gössl, M; Buck, T; Wilde, B; Heemann, U; Kribben, A; Witzke, O
Imatinib ameliorates fibrosis in uraemic cardiac disease in BALB/c without improving cardiac function.
Cardiovascular disease is one of the major causes of mortality and morbidity in patients with end-stage renal disease (ESRD). It is characterized by multiple left ventricular abnormalities, referred to as'uraemic cardiomyopathy'. The aim of the study was to investigate uraemic cardiac disease in a mouse model of chronic renal failure induced by subtotal nephrectomy and to evaluate the impact of the tyrosine kinase inhibitor imatinib and its antifibrotic as well as functional properties on the extent of the disease.Male BALB/c mice were sham operated (SH) or subtotally nephrectomized and either left untreated (5/6) or treated with imatinib (5/6+I: 10 mg/kg/day p.o.) for up to 24 weeks. Cardiac and arterial structure and function were analysed using echocardiography, histology, extent of lipid peroxidation and myography, respectively.Subtotal nephrectomy resulted in cardiac dysfunction characterized by reduced fractional shortening (SH: 21.6 +/- 4.7%; 5/6: 11.1 +/- 2.4%; 5/6+I: 8.4 +/- 2.7%; P< 0.05) and ejection fraction (SH: 38.8 +/- 4.5%; 5/6: 26.1 +/- 2.8%; 5/6+I: 18.6 +/- 2.6%; P< 0.05) after 24 weeks. This was associated with impaired endothelium-dependent vasodilatation in mesenteric resistance vessels and elevated cardiac malondialdehyde concentrations as a marker of lipid peroxidation. In this model, the continuous application of the tyrosine kinase inhibitor imatinib was associated with less myocardial fibrosis (SH: 2.52 +/- 0.34%; 5/6: 5.50 +/- 0.18%; 5/6+I: 3.52 +/- 0.52%; P< 0.05), but did not preserve myocardial function.Uraemic cardiac disease in BALB/c results in fibrosis, oxidative damage and endothelial dysfunction. However, the anti-fibrotic activity of imatinib did not ameliorate cardiac dysfunction. Thus, our data suggest that uraemic cardiac disease in this mouse model is driven by oxidative damage and endothelial dysfunction.