Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia.
BACKGROUND
Hypercholesterolaemia (HC), an independent risk factor for renal injury, is associated with formation of oxidized low-density-lipoprotein (ox-LDL), increased oxidative-stress and renal inflammation. HMG-CoA-reductase inhibitors are commonly used in HC, but their effects on renal haemodynamics and function in HC are poorly understood.


METHODS
Pigs were studied after a 12-week normal diet, a 2% high-cholesterol diet (HC) or an HC diet supplemented with simvastatin (HC+simvastatin, 80 mg/day) (n=6-8 each group). Renal haemodynamics and function were quantified in vivo with electron-beam computed tomography (EBCT). Shock-frozen renal tissue was subsequently studied using immunohistochemistry.


RESULTS
LDL cholesterol was similarly increased in HC and HC+simvastatin. Simvastatin-treated animals showed increased expression of endothelial nitric-oxide-synthase (eNOS), and decreased expression of the ox-LDL receptor LOX-1 in renal endothelial cells. Simvastatin also decreased tubular immunoreactivity of inducible-NOS, nitrotyrosine, nuclear-factor-kappaB, and tubuloglomerular trichrome staining. These were associated with a significant increase in cortical (6.1+/-0.1 vs 5.0+/-0.3 and 5.0+/-0.1 ml/min/cc, respectively, P<0.001) and medullary perfusion in HC+simvastatin compared to normal and HC.


CONCLUSIONS
Simvastatin attenuated the inflammatory and pro-oxidative environment as well as fibrosis in kidneys in pigs with diet-induced HC, in association with enhanced renal perfusion. These cholesterol-lowering-independent changes imply novel renoprotective effects of statins in the setting of HC and atherosclerosis.
Wilson
Stephanie H
SH
Division of Hypertension, Mayo Clinic, Rochester, MN 55905, USA.
Chade
Alejandro R
AR
Feldstein
Ariel
A
Sawamura
Tatsuya
T
Napoli
Claudio
C
Lerman
Amir
A
Lerman
Lilach O
LO
D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000188:drug therapy*; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D007677:Kidney Function Tests; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011336:Probability; D011897:Random Allocation; D011973:Receptors, LDL / Q000378:metabolism; D051131:Receptors, Oxidized LDL; D012016:Reference Values; D012079:Renal Circulation / Q000187:drug effects; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; C002744:3-nitrotyrosine; D014443:Tyrosine; D019821:Simvastatin; D019001:Nitric Oxide Synthase