Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin

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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.

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This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2013M3A9B5075839 and NRF-2015R1A2A1A10054384; M-K Kwak). This study was also supported by the BK21 Plus Creative Leader Program for Pharmacomics-based Future Pharmacy. We thank Dr. Tae Hwe Heo, Dr. Jae Hong Seo, and Dr. Soo Kyung Bae at The Catholic University of Korea, and Dr. Sukhyang Lee at Ajou University for their contributions to study design.

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Correspondence to Mi-Kyoung Kwak.

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The authors declare that they have no competing interests.

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Jeong-hyeon Park and Bo-hyun Choi have contributed equally to this work.

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Park, J., Choi, B., Ku, S. et al. Amelioration of high fat diet-induced nephropathy by cilostazol and rosuvastatin. Arch. Pharm. Res. 40, 391–402 (2017) doi:10.1007/s12272-017-0889-y

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  • Chronic kidney disease
  • High fat diet
  • Cilostazol
  • Rosuvastatin
  • Ho-1