Simvastatin decreases endothelial progenitor cell apoptosis in the kidney of hypertensive hypercholesterolemic pigs.
OBJECTIVE
Hypertension and hypercholesterolemia might interfere with renal repair mechanisms. We hypothesized that simvastatin improves the survival of endothelial progenitor cells (EPC) in the renal microenvironment imposed by concurrent renovascular hypertension and dietary hypercholesterolemia (HTC).


RESULTS
Pigs were studied after 12 weeks of no intervention (n=6), HTC (n=6), or HTC+ oral simvastatin supplementation (80 mg/day, n=5). EPC were also isolated and studied in vitro after exposure to the proapoptotic oxidized low-density lipoprotein with or without coincubation with simvastatin. Renal hemodynamics, function, and endothelial function were evaluated in vivo, and the number of CD34+/KDR+ EPC, apoptosis, oxidative stress, inflammation, and fibrosis in renal tissue studied ex vivo. Compared with normal kidney, the HTC kidney showed endothelial dysfunction and increased oxidative stress, interstitial macrophage filtration, and fibrosis. The number of EPC in the kidney increased, as did their apoptosis (0.85+/-0.24% versus 0.22+/-0.07%, P<0.05 versus normal). Simvastatin did not affect blood pressure, cholesterol levels, basal renal function, or number of renal EPC in HTC, but it improved endothelial function; blunted renal oxidative stress, inflammation, and fibrosis; and attenuated EPC apoptosis (to 0.37+/-0.09%, P<0.05 versus HTC). Simvastatin also significantly decreased oxidized low-density lipoprotein-induced EPC apoptosis in vitro.


CONCLUSIONS
EPC are recruited but undergo apoptosis in the HTC kidney, likely because of a hostile microenvironment. Simvastatin rescues renal repair mechanisms in HTC and counteracts renal damage, which may account for its protective effects on the kidney during exposure to cardiovascular risk factors.
Lavi
Ronit
R
Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Zhu
Xiang-Yang
XY
Chade
Alejandro R
AR
Lin
Jing
J
Lerman
Amir
A
Lerman
Lilach O
LO
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D006439:Hemodynamics / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D007668:Kidney / Q000098:blood supply*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034421:Sus scrofa
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D019821:Simvastatin