Oxidative stress after uninephrectomy alters heart morphology in the apolipoprotein E -/- mouse.
OBJECTIVE
Even minor reduction in glomerular filtration rate accelerates atherogenesis and increases cardiovascular risk. The current study on the apolipoprotein E -/- mouse was designed to investigate whether nephron reduction by uninephrectomy causes cardiac remodeling and whether this is prevented by antioxidative treatment.


METHODS
We randomized apolipoprotein E -/- mice to undergo uninephrectomy or sham operation and subsequent treatment with either Tempol, Ebselen, Trandolapril, or a combination of Tempol and Trandolapril. After 12 weeks, the experiment was terminated by perfusion fixation under anesthesia. The myocardium was analyzed by morphometry. Additionally, the expression of endothelial nitric oxide synthase, transforming growth factor-beta1, vascular endothelial growth factor, flt-1, collagen I and presence of nitrotyrosine were assessed using immunohistochemistry or western blotting.


RESULTS
Untreated uninephrectomized animals had lower capillary length density and higher volume fraction of interstitial tissue in the myocardium and bigger plaques in aorta compared with those who underwent sham operation. These changes did not develop in uninephrectomized animals treated with Tempol, Ebselen, Trandolapril, or Tempol + Trandolapril. In untreated uninephrectomized mice, the presence of nitrotyrosine and the expression of transforming growth factor-beta1, vascular endothelial growth factor, and collagen I were more marked. This was ameliorated by Tempol, Ebselen, Trandolapril, and Tempol + Trandolapril.


CONCLUSIONS
We conclude that in the apolipoprotein E -/- mouse, even minor reduction in renal function, for example, by uninephrectomy, causes remodeling of the heart. This was ameliorated to a similar extent by antioxidants and angiotensin-converting enzyme inhibition.
Department of Internal Medicine, Division of Nephrology, University of Heidelberg, Heidelberg, Germany. g.piecha@gmx.de
Grzegorz
G
Piecha
Nadezda
N
Koleganova
Marie-Luise
ML
Gross
Aman
A
Geldyyev
Eberhard
E
Ritz
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D003497:Cyclic N-Oxides / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D020868:Gene Silencing; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013113:Spin Labels; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D001057:Apolipoproteins E; D003497:Cyclic N-Oxides; D007211:Indoles; D013113:Spin Labels; C052035:trandolapril; C001803:tempol