title: Ezetimibe alone or in combination with pitavastatin prevents kidney dysfunction in 5/6 nephrectomized rats fed high-cholesterol.
abstract: We attempted to elucidate the relationship between cholesterol absorption and kidney damage by investigating the renoprotective effect of ezetimibe, a cholesterol absorption inhibitor, in 5/6 nephrectomized rats (Nx). The Nx or sham-operated rats (Sham) were fed 1% high-cholesterol diet (HC) containing ezetimibe (10 mg/[kg d]), pitavastatin (3 mg/[kg d]), or both for 8 weeks. Pathological changes, endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA), and oxidative stress were assessed in the kidney. The Sham fed HC exhibited hypercholesterolemia and glomerulosclerosis with macrophage infiltration in the kidney, and ezetimibe attenuated these changes. The Nx exhibited hypercholesterolemia, increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), glomerulosclerosis with macrophage infiltration and interstitial fibrosis, and downregulation of eNOS mRNA. The HC increased cholesterol further and worsened the kidney damage with increased 8-OHdG. Ezetimibe attenuated the hypercholesterolemia, kidney dysfunction, and pathological changes. The beneficial effects of ezetimibe were significantly associated with reduced 8-OHdG (P < .01). Pitavastatin did not reduce cholesterol or 8-OHdG, but it did significantly suppress the kidney damage with upregulated eNOS mRNA by 2.5-fold (P < .02). The combination of ezetimibe and pitavastatin synergistically ameliorated the kidney damage. The kidney dysfunction and pathological changes were significantly associated with cholesterol, markers of cholesterol absorption (campesterol and cholestanol), and 8-OHdG (P < .001-.05). Multiple regression analysis revealed that the markers of cholesterol absorption were independently associated with the kidney damage. Ezetimibe confers renoprotective effects by inhibiting cholesterol absorption, which in turn reduces oxidative stress; and pitavastatin additively ameliorates kidney damage by increasing NO production via mechanisms independent of cholesterol reduction.
authors.affiliation: Department of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001384:Azetidines / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D008076:Cholesterol, HDL / Q000097:blood; D003404:Creatinine / Q000378:metabolism; D003849:Deoxyguanosine / Q000378:metabolism; D000069438:Ezetimibe; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D009392:Nephrectomy; D011507:Proteinuria / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood; D000097382:CD68 Molecule
chemical_list: D000924:Anticholesteremic Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001384:Azetidines; D002784:Cholesterol; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D003404:Creatinine; D003849:Deoxyguanosine; D000069438:Ezetimibe; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D012313:RNA; D014280:Triglycerides; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C108475:pitavastatin