title: Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin.
abstract: Multiple comorbidities of metabolic disorders are associated with facilitated chronic kidney disease progression. Anti-platelet cilostazol is used for the treatment of peripheral artery disease. In this study, we investigated the potential beneficial effects of cilostazol and rosuvastatin on metabolic disorder-induced renal dysfunctions. C57BL/6 mice that received high fat diet (HFD) for 22 weeks and a low dose of streptozotocin (STZ, 40 mg/kg) developed albuminuria and had increased urinary cystatin C excretion, and cilostazol treatment (13 weeks) improved these markers. Histopathological changes, including glomerular mesangial expansion, tubular vacuolization, apoptosis, and lipid accumulation were ameliorated by cilostazol treatment. Tubulointerstitial fibrosis that was indicated by the increases in collagen and transforming growth factor-β1 subsided by cilostazol. Renoprotective effects were also observed in rosuvastatin-treated mice, and combinatorial treatment with cilostazol and rosuvastatin demonstrated enhanced ameliorative effects in histopathological evaluations. Notably, repressed renal heme oxygenase-1 (Ho-1) level in HFD/STZ mice was restored in cilostazol group. Further, we demonstrated that cilostazol enhanced Nrf2/Ho-1 signaling in cultured proximal tubular epithelial cells. Collectively, these results suggest the potential advantageous use of cilostazol as an adjunctive therapy with statins for the amelioration of metabolic disorder-associated renal injury.
authors.affiliation: Department of Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Bo-Hyun
authors.initials: BH
authors.lastname: Choi
authors.affiliation: College of Korean Medicine, Daegu Haany University, Hannydae-ro 1, Gyeongsan, Gyeonsangbuk-do, 712-715, Republic of Korea.
authors.forename: Sae-Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: Department of Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Kyeong-Ah
authors.initials: KA
authors.lastname: Jung
authors.affiliation: Department of Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.|College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea.
authors.forename: Euichaul
authors.initials: E
authors.lastname: Oh
authors.affiliation: Department of Pharmacy, Graduate School of The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea. mkwak@catholic.ac.kr.|College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Bucheon, Gyeonggi-do, 420-743, Republic of Korea. mkwak@catholic.ac.kr.
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
mesh_terms: D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D000077407:Cilostazol; D055316:Cystatin C / Q000652:urine; D059305:Diet, High-Fat / Q000009:adverse effects*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000209:etiology* / Q000652:urine; D000068718:Rosuvastatin Calcium / Q000627:therapeutic use*; D013311:Streptozocin / Q000633:toxicity; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D055316:Cystatin C; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D013311:Streptozocin; D000068718:Rosuvastatin Calcium; D051547:Heme Oxygenase-1; D000077407:Cilostazol
keywords: Chronic kidney disease; Cilostazol; High fat diet; Ho-1; Rosuvastatin