Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia.
We tested the hypothesis that statins would decrease renal injury in renal artery stenosis (RAS) by restoring angiogenesis and attenuating intrarenal microvascular (IMV) remodeling. Single-kidney hemodynamics and function were quantified using electron-beam-computed tomography (CT) in normocholesterolemic pigs after 12 wk of experimental RAS, RAS supplemented with simvastatin (RAS+simvastatin), and normal controls. Renal circulation was also studied in vivo using angiography and ex vivo using a unique 3D micro-CT imaging technique. Angiogenic and remodeling pathways were subsequently explored in renal tissue. Blood pressure and the degree of stenosis were similarly increased in RAS groups. Simvastatin in RAS enhanced both intrarenal angiogenesis and peri-stenosis arteriogenesis and increased the expression of angiogenic growth factors and hypoxia-inducible factor-1alpha. Furthermore, simvastatin decreased tissue-transglutaminase expression and IMV inward remodeling, restored IMV endothelial function, decreased fibrogenic activity, and improved renal function. Chronic simvastatin supplementation promoted angiogenesis in vivo, decreased ischemia-induced IMV remodeling, and improved IMV function in the stenotic kidney, independent of lipid lowering. These novel renoprotective effects suggest a role for simvastatin in preserving the ischemic kidney in chronic RAS.
Chade
Alejandro R
AR
Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First St. S.W., Rochester, Minnesota 55905, USA.
Zhu
Xiangyang
X
Mushin
Oren P
OP
Napoli
Claudio
C
Lerman
Amir
A
Lerman
Lilach O
LO
D042501:Angiogenic Proteins / Q000032:analysis; D000818:Animals; D001794:Blood Pressure; D002908:Chronic Disease; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008833:Microcirculation / Q000187:drug effects*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012078:Renal Artery Obstruction / Q000150:complications*; D019821:Simvastatin / Q000494:pharmacology*; D013552:Swine; D011503:Transglutaminases / Q000032:analysis
D042501:Angiogenic Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019821:Simvastatin; D011503:Transglutaminases