Imatinib ameliorates fibrosis in uraemic cardiac disease in BALB/c without improving cardiac function.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Baumann
Marcus
M
Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Germany.
Leineweber
Kirsten
K
Tewiele
Marion
M
Wu
Kun
K
Türk
Tobias R
TR
Su
Song
S
Gössl
Mario
M
Buck
Thomas
T
Wilde
Benjamin
B
Heemann
Uwe
U
Kribben
Andreas
A
Witzke
Oliver
O
D000818:Animals; D001549:Benzamides; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000503:physiopathology; D005355:Fibrosis; D000068877:Imatinib Mesylate; D007676:Kidney Failure, Chronic / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009392:Nephrectomy; D018384:Oxidative Stress; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology*; D014511:Uremia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases