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

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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.

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References

  1. Abraham NG, Kushida T, Mcclung J, Weiss M, Quan S, Lafaro R, Darzynkiewicz Z, Wolin M (2003) Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res 93:507–514

  2. Abraham NG, Cao J, Sacerdoti D, Li X, Drummond G (2009) Heme oxygenase: the key to renal function regulation. Am J Physiol Renal Physiol 297:F1137–1152

  3. Böttinger EP (2007) TGF-β in renal injury and disease. Semin nephrol 27:309–320. doi:10.1016/j.semnephrol.2007.02.009

  4. Braun L, Sood V, Hogue S, Lieberman B, Copley-Merriman C (2012) High burden and unmet patient needs in chronic kidney disease. Int J Nephrol Renovasc Dis 5:151–163

  5. Bruce CR, Carey AL, Hawley JA, Febbraio MA (2003) Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Diabetes 52:2338–2345

  6. Campese VM (2014) Dyslipidemia and progression of kidney disease: role of lipid-lowering drugs. Clin Exp Nephrol 18:291–295

  7. Chigusa Y, Kawasaki K, Kondoh E, Mogami H, Ujita M, Fujita K, Tatsumi K, Takeda S, Konishi I (2016) Simvastatin inhibits oxidative stress via the activation of nuclear factor erythroid 2-related factor 2 signaling in trophoblast cells. J Obstet Gynaecol Res 42:36–43

  8. Dawson DL (2001) Comparative effects of cilostazol and other therapies for intermittent claudication. Am J Cardiol 87:19d–27d

  9. De Zeeuw D, Anzalone DA, Cain VA, Cressman MD, Heerspink HJ, Molitoris BA, Monyak JT, Parving HH, Remuzzi G, Sowers JR, Vidt DG (2015) Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial. Lancet Diabetes Endocrinol 3:181–190

  10. Declèves A-E, Mathew AV, Cunard R, Sharma K (2011) AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol 22:1846–1855

  11. Deji N, Kume S, Araki S-I, Soumura M, Sugimoto T, Isshiki K, Chin-Kanasaki M, Sakaguchi M, Koya D, Haneda M (2009) Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am J Physiol Renal Physiol 296:F118–F126

  12. Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Kottgen A, Levey AS, Levin A (2013) Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 382:158–169

  13. Eddy AA (1996) Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 7:2495–2508

  14. Elmarakby AA, Faulkner J, Baban B, Saleh MA, Sullivan JC (2012a) Induction of hemeoxygenase-1 reduces glomerular injury and apoptosis in diabetic spontaneously hypertensive rats. Am J Physiol Renal Physiol 302:F791–800

  15. Elmarakby AA, Faulkner J, Baban B, Sullivan JC (2012b) Induction of hemeoxygenase-1 reduces renal oxidative stress and inflammation in diabetic spontaneously hypertensive rats. Int J Hypertens 2012:957235

  16. Fiseha T (2015) Urinary biomarkers for early diabetic nephropathy in type 2 diabetic patients. Biomark Res 3:16

  17. Fraser SD, Roderick PJ, May CR, Mcintyre N, Mcintyre C, Fluck RJ, Shardlow A, Taal MW (2015) The burden of comorbidity in people with chronic kidney disease stage 3: a cohort study. BMC Nephrol 16:193

  18. Gilbert ER, Fu Z, Liu D (2011) Development of a nongenetic mouse model of type 2 diabetes. Exp Diabetes Res 2011:416254

  19. Giunti S, Calkin AC, Forbes JM, Allen TJ, Thomas MC, Cooper ME, Jandeleit-Dahm KA (2010) The pleiotropic actions of rosuvastatin confer renal benefits in the diabetic Apo-E knockout mouse. Am J Physiol Renal Physiol 299:F528–535

  20. Grosser N, Erdmann K, Hemmerle A, Berndt G, Hinkelmann U, Smith G, Schroder H (2004) Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1. Biochem Biophys Res Commun 325:871–876

  21. Grouse JR 3rd, Allan MC, Elam MB (2002) Clinical manifestation of atherosclerotic peripheral arterial disease and the role of cilostazol in treatment of intermittent claudication. J Clin Pharmacol 42:1291–1298

  22. Habeos IG, Ziros PG, Chartoumpekis D, Psyrogiannis A, Kyriazopoulou V, Papavassiliou AG (2008) Simvastatin activates Keap1/Nrf2 signaling in rat liver. J Mol Med 86:1279–1285

  23. Herget-Rosenthal S, Marggraf G, Husing J, Goring F, Pietruck F, Janssen O, Philipp T, Kribben A (2004) Early detection of acute renal failure by serum cystatin C. Kidney Int 66:1115–1122

  24. Hsieh CH, Rau CS, Hsieh MW, Chen YC, Jeng SF, Lu TH, Chen SS (2008) Simvastatin-induced heme oxygenase-1 increases apoptosis of Neuro 2A cells in response to glucose deprivation. Toxicol Sci 101:112–121

  25. Hwang M, Kim HJ, Noh HJ, Chang YC, Chae YM, Kim KH, Jeon JP, Lee TS, Oh HK, Lee YS, Park KK (2006) TGF-beta1 siRNA suppresses the tubulointerstitial fibrosis in the kidney of ureteral obstruction. Exp Mol Pathol 81:48–54

  26. Ito M, Kondo Y, Nakatani A, Hayashi K, Naruse A (2001) Characterization of low dose streptozotocin-induced progressive diabetes in mice. Environ Toxicol Pharmacol 9:71–78

  27. Kang SJ, You A, Kwak MK (2011) Suppression of Nrf2 signaling by angiotensin II in murine renal epithelial cells. Arch Pharm Res 34:829–836

  28. Kasahara M, Nakagawa T, Yokoi H, Kuwabara T, Yasuno S, Mori K, Mukoyama M, Ueshima K (2014) Do statins play a role in renoprotection? Clin Exp Nephrol 18:282–285

  29. Kie JH, Kapturczak MH, Traylor A, Agarwal A, Hill-Kapturczak N (2008) Heme oxygenase-1 deficiency promotes epithelial-mesenchymal transition and renal fibrosis. J Am Soc Nephrol 19:1681–1691

  30. Kim JH, Yang JI, Jung MH, Hwa JS, Kang KR, Park DJ, Roh GS, Cho GJ, Choi WS, Chang SH (2006) Heme oxygenase-1 protects rat kidney from ureteral obstruction via an antiapoptotic pathway. J Am Soc Nephrol 17:1373–1381

  31. Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, Ku SK, Jung Y, Kwak MK (2011) NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer Res 71:2260–2275

  32. Kim DH, Choi BH, Ku SK, Park JH, Oh E, Kwak MK (2016) Beneficial effects of Sarpogrelate and Rosuvastatin in high fat diet/Streptozotocin-induced nephropathy in mice. PLoS ONE 11:e0153965

  33. Kume S, Uzu T, Araki S, Sugimoto T, Isshiki K, Chin-Kanasaki M, Sakaguchi M, Kubota N, Terauchi Y, Kadowaki T, Haneda M, Kashiwagi A, Koya D (2007) Role of altered renal lipid metabolism in the development of renal injury induced by a high-fat diet. J Am Soc Nephrol 18:2715–2723

  34. Kwak MK, and Kensler TW (2009) Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol (in press)

  35. Landray MJ, Haynes RJ (2008) Commentary: controversies in NICE guidance on chronic kidney disease. BMJ 337:a1793

  36. Lee SC, Han SH, Li JJ, Lee SH, Jung DS, Kwak SJ, Kim SH, Kim DK, Yoo TH, Kim JH, Chang SH, Han DS, Kang SW (2009) Induction of heme oxygenase-1 protects against podocyte apoptosis under diabetic conditions. Kidney Int 76:838–848

  37. Levey AS, Eckardt K-U, Tsukamoto Y, Levin A, Coresh J, Rossert J, Zeeuw DD, Hostetter TH, Lameire N, Eknoyan G (2005) Definition and classification of chronic kidney disease: a position statement from kidney disease: improving global outcomes (KDIGO). Kidney Int 67:2089–2398

  38. Li W, Kong AN (2009) Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 48:91–104

  39. Li H, Zhang L, Wang F, Shi Y, Ren Y, Liu Q, Cao Y, Duan H (2011) Attenuation of glomerular injury in diabetic mice with tert-butylhydroquinone through nuclear factor erythroid 2-related factor 2-dependent antioxidant gene activation. Am J Nephrol 33:289–297

  40. Liu Y (2006) Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 69:213–217

  41. Liu Y (2011) Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7:684–696

  42. Margetts PJ, Bonniaud P, Liu L, Hoff CM, Holmes CJ, West-Mays JA, Kelly MM (2005) Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol 16:425–436

  43. Meguid El Nahas A, Bello AK (2005) Chronic kidney disease: the global challenge. Lancet 365:331–340

  44. Park SY, Lee SW, Shin HK, Chung WT, Lee WS, Rhim BY, Hong KW, Kim CD (2010) Cilostazol enhances apoptosis of synovial cells from rheumatoid arthritis patients with inhibition of cytokine formation via Nrf2-linked heme oxygenase 1 induction. Arthritis Rheum 62:732–741

  45. Park SY, Lee SW, Baek SH, Lee SJ, Lee WS, Rhim BY, Hong KW, Kim CD (2011) Induction of heme oxygenase-1 expression by cilostazol contributes to its anti-inflammatory effects in J774 murine macrophages. Immunol Lett 136:138–145

  46. Pohlers D, Brenmoehl J, Loffler I, Muller CK, Leipner C, Schultze-Mosgau S, Stallmach A, Kinne RW, Wolf G (2009) TGF-beta and fibrosis in different organs—molecular pathway imprints. Biochim Biophys Acta 1792:746–756

  47. Reidy K, Kang HM, Hostetter T, Susztak K (2014) Molecular mechanisms of diabetic kidney disease. J Clin Invest 124:2333–2340

  48. Rogers KC, Oliphant CS, Finks SW (2015) Clinical efficacy and safety of cilostazol: a critical review of the literature. Drugs 75:377–395

  49. Sato M, Muragaki Y, Saika S, Roberts AB, Ooshima A (2003) Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 112:1486–1494

  50. Schaeffner ES, Kurth T, Curhan GC, Glynn RJ, Rexrode KM, Baigent C, Buring JE, Gaziano JM (2003) Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 14:2084–2091

  51. Shevalye H, Lupachyk S, Watcho P, Stavniichuk R, Khazim K, Abboud HE, Obrosova IG (2012) Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology 153:1152–1161

  52. Shin JH, Lee CW, Oh SJ, Yun J, Kang MR, Han SB, Park H, Jung JC, Chung YH, Kang JS (2014) Hepatoprotective effect of aged black garlic extract in rodents. Toxicol Res 30:49–54

  53. Sirtori CR (2014) The pharmacology of statins. Pharmacol Res 88:3–11

  54. Son JY, Kang YJ, Kim KS, Kim TH, Lim SK, Lim HJ, Jeong TC, Choi DW, Chung KH, Lee BM, Kim HS (2014) Evaluation of renal toxicity by combination exposure to melamine and cyanuric acid in male sprague-dawley rats. Toxicol Res 30:99–107

  55. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 52:313–320

  56. Srisook K, Kim C, Cha YN (2005) Molecular mechanisms involved in enhancing HO-1 expression: de-repression by heme and activation by Nrf2, the “one-two” punch. Antioxid Redox Signal 7:1674–1687

  57. Strutz F, Zeisberg M (2006) Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol 17:2992–2998

  58. Tamura Y, Murayama T, Minami M, Yokode M, Arai H (2011) Differential effect of statins on diabetic nephropathy in db/db mice. Int J Mol Med 28:683–687

  59. Tang WH, Lin FH, Lee CH, Kuo FC, Hsieh CH, Hsiao FC, Hung YJ (2014) Cilostazol effectively attenuates deterioration of albuminuria in patients with type 2 diabetes: a randomized, placebo-controlled trial. Endocrine 45:293–301

  60. Tohma T, Shimabukuro M, Oshiro Y, Yamakawa M, Shimajiri Y, Takasu N (2004) Cilostazol, a phosphodiesterase inhibitor, reduces microalbuminuria in the insulin-resistant Otsuka Long-Evans Tokushima fatty rat. Metabolism 53:1405–1410

  61. Tracz MJ, Alam J, Nath KA (2007) Physiology and pathophysiology of heme: implications for kidney disease. J Am Soc Nephrol 18:414–420

  62. Wang X, Yan L, Chen W, Xu L, Zhang X (2009) The renal protective effects of cilostazol on suppressing pathogenic thrombospondin-1 and transforming growth factor-beta expression in streptozotocin-induced diabetic rats. J Int Med Res 37:145–153

  63. Wei P, Grimm PR, Settles DC, Balwanz CR, Padanilam BJ, Sansom SC (2009) Simvastatin reverses podocyte injury but not mesangial expansion in early stage type 2 diabetes mellitus. Ren Fail 31:503–513

  64. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210

  65. Yeh YH, Kuo CT, Chang GJ, Chen YH, Lai YJ, Cheng ML, Chen WJ (2015) Rosuvastatin suppresses atrial tachycardia-induced cellular remodeling via Akt/Nrf2/heme oxygenase-1 pathway. J Mol Cell Cardiol 82:84–92

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Acknowledgements

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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Keywords

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