Renal effects of HMG-CoA reductase inhibition in a rat model of chronic inhibition of nitric oxide synthesis.
OBJECTIVE
In addition to their lipid-lowering effects, HMG-CoA reductase inhibitors (statins) induce a variety of pleiotropic actions that have been recently studied in the area of cardiovascular and renal protection. In the present studies we sought to determine whether statins retain beneficial effects in the experimental model of NO deficiency achieved by chronic administration of a pressor dose of L-arginine analogue N-nitro-L-arginine-methyl ester (L-NAME).


METHODS
To address this issue, blood pressure (BP), renal function (GFR), and albuminuria were determined in rats treated for 4 weeks with L-NAME, L-NAME + atorvastatin (ATO), and in untreated controls. In addition, renal cortical protein expression of caveolin 1 (CAV1), vascular endothelial growth factor (VEGF), and activity of RhoA were also determined.


RESULTS
L-NAME administration resulted in sustained elevation of BP, decreased GFR, and in higher albuminuria as compared to control animals. Co-administration of ATO with L-NAME normalized albuminuria and prevented decreases in GFR in L-NAME rats without having an impact on pressor effects of L-NAME. CAV1 protein expression was similar in all groups of rats. In contrast, VEGF expression and RhoA activity was increased in L-NAME-treated animals, and normalized with co-administration of ATO.


CONCLUSIONS
Treatment with ATO exerts early nephroprotective effects in the NO-deficient model of hypertension. These effects could be mediated by amelioration of VEGF expression and reduction of RhoA activity.
Lecian
Dalibor
D
Department of Nephrology, Institute for Clinical and Experimental Medicine, Charles University, Prague, Czech Republic.
Demova
Hana
H
Lodererova
Alena
A
Zdychova
Jana
J
Kluckova
Hana
H
Teplan
Vladimir
V
Voska
Ludek
L
Komers
Radko
R
D000419:Albuminuria / Q000188:drug therapy; D000704:Analysis of Variance; D000818:Animals; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects*; D051242:Caveolin 1 / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control; D007674:Kidney Diseases / Q000517:prevention & control; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D023421:Models, Animal; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C495537:Cav1 protein, rat; D051242:Caveolin 1; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D009569:Nitric Oxide; D000069059:Atorvastatin; D020742:rhoA GTP-Binding Protein; D019331:NG-Nitroarginine Methyl Ester