Effect of simvastatin in apolipoprotein E deficient mice with surgically induced chronic renal failure.
OBJECTIVE
Patients with a surgically reduced renal mass are at increased risk for progressive renal failure, which often requires renal replacement therapy or kidney transplantation. We investigated the effects of simvastatin supplementation on uremia enhanced atherosclerosis and vascular calcification in apoE(-/-) (apolipoprotein E deficient) mice (Charles Rivers Laboratories, Wilmington, Massachusetts) with or without superimposed chronic kidney disease.


METHODS
The mice were randomly assigned to 4 groups, including 2 groups with normal renal function (simvastatin vs control in 13 mice) and the other 2 with surgically created chronic kidney disease (simvastatin vs control in 18). Simvastatin (100 mg/kg) was administered by daily oral gavage for 4 weeks.


RESULTS
Simvastatin treatment did not prevent uremia accelerated atherosclerosis in chronic kidney disease apoE(-/-) mice, nor did it retard atherosclerosis progression in control nonchronic kidney disease mice. However, aortic plaques in simvastatin treated chronic kidney disease mice showed significantly less calcification than those in controls with chronic kidney disease (p <0.03). In addition, the increase of aortic nitrotyrosine staining in mice with chronic kidney disease was prevented by simvastatin treatment (p <0.02). Serum total cholesterol was increased to a similar extent in the 2 chronic kidney disease groups compared with that in the nonchronic kidney disease groups. The beneficial effect of simvastatin on uremia enhanced vascular calcification in apoE(-/-) mice with chronic kidney disease was observed despite the absence of changes in uremia accelerated atherosclerosis progression, serum total cholesterol levels or osteopontin and alkaline phosphatase expression.


CONCLUSIONS
Our observation opens the possibility of a cholesterol independent action of statins on vascular calcification via a decrease in oxidative stress.
Ivanovski
Ognen
O
Institut National en Santé et Recherche Médicale Unit 845, Paris, France.
Szumilak
Dorota
D
Nguyen-Khoa
Thao
T
Nikolov
Igor G
IG
Joki
Nobuhiko
N
Mothu
Nadya
N
Maizel
Julien
J
Westenfeld
Ralf
R
Ketteler
Marcus
M
Lacour
Bernard
B
Drüeke
Tilman B
TB
Massy
Ziad A
ZA
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy*; D002114:Calcinosis / Q000188:drug therapy; D004195:Disease Models, Animal; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use
D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin