Protection of renal damage by HMG-CoA inhibitors: A comparative study between atorvastatin and rosuvastatin

Document Type: Original Article


1 Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

2 Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Urology and Nephrology Research Center, Beheshti University of Medical Sciences, Tehran, Iran

4 Food and Drug Safety Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

5 Stem Cell Research Center, Tabriz University of Medical Sciences. Tabriz, Iran

6 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s): Hypercholesterolemia is a common metabolic disorder in developing and developed countries and is associated with the increased rates of chronic kidney disease (CKD). Statin therapy could reduce cholesterol synthesis as well as progression of CKD. Diversity between statins causes variety in pharmacokinetics and pharmacodynamics and also their pleiotropic effects. In the present investigation we aimed to evaluate the protective potentials of both atorvastatin (Ator) (as lipid-soluble statin) and rosuvastatin (Ros) (as water-soluble statin) against renal histopathological damages in the high cholesterol diet induced hypercholesterolemic rats (HCDIHR).
Materials and Methods: Serum lipid profile, oxidized low density lipoprotein (OX-LDL), malondialdehyde (MDA), urea and creatinine levels, as well as renal histopathology were evaluated.
Results: While Ros acted better than Ator to reduce serum low density lipoprotein cholesterol (LDL-C) (P<0.01), atherogenic index (AI) (P<0.01), MDA (P<0.01), and OX-LDL (P<0.01); no significant differences were noted in their cholesterol (P=0.72), triglyceride (TG) (P=0.79), and very low density lipoprotein cholesterol lowering (VLDL-C) (P=0.79) and high density lipoprotein cholesterol elevating effects (HDL-C) (P=0.72). Ator was more effective to reduce renal histopathologic indices compared to Ros, including accumulation of lipid droplet, glomerular foam cells, mesangial cell proliferation, renal hemorrhage, and tubulointerstitial damages in the kidneys of diet induced hypercholesterolemic rats.
Conclusion: The findings underline that the lipophilic Ator may performs better than Ros in attenuating renal damages in HCDIHR.


1. Munshi RP, Joshi SG, Rane BN. Development of an experimental diet model in rats to study hyperlipidemia and insulin resistance, markers for coronary heart disease. Indian J Pharmacol 2014; 46:270-276.
2. Csonka C, Sárközy M, Pipicz M, Dux L, Csont T. Modulation of hypercholesterolemia-induced oxidative/nitrative stress in the heart. Oxid Med Cell Longev 2016; 2016.
3. Kose E, An T, Kikkawa A, Matsumoto Y, Hayashi H. Effects on serum uric acid by difference of the renal protective effects with atorvastatin and rosuvastatin in chronic kidney disease patients. Biol. Pharm. Bull 2014; 37:226-231.
4. Belguithhadriche O, Bouaziz M, Jamoussi K, Elfeki A, Makniayedi F. Renoprotective effects of fenugreek seeds against oxidative stress in hypercholesterolemic fed Rats. J Med Food 2014 2014; 8:382-385.
5. Sundaram M, Palaneeswari S, Nagarajan S, Devi M, Jagdeeshwaran A. Chronic kidney disease - effect of oxidative stress. Chin J Biol 2014; 2014.
6. Jaqueto M, Delfino VDA, Bortolasci CC, Barbosa DS, Morimoto HK, Frange RFN, et al. Are PTH levels related to oxidative stress and inflammation in chronic kidney disease patients on hemodialysis? J Bras Nefrol 2016; 38:288-295.
7. Elhemely MA, Omar HA, Ain-Shoka AA, El-Latif HAA, Abo-youssef AM, El Sherbiny GA. Rosuvastatin and ellagic acid protect against isoproterenol-induced myocardial infarction in hyperlipidemic rats. BJBAS 2014; 3:239-246.
8. Lee HS, Song CY. Oxidized low-density lipoprotein and oxidative stress in the development of glomerulosclerosis. Am J Nephrol 2009; 29:62-70.
9. Lovrić J, Mesić M, Macan M, Koprivanac M, Kelava M, Bradamante V. Measurement of malondialdehyde (MDA) level in rat plasma after simvastatin treatment using two different analytical methods. Period Biol 2008; 110:63-68.
10. Sastre C, Rubio-Navarro A, Buendía I, Gómez-Guerrero C, Blanco J, Mas S, et al. Hyperlipidemia-associated renal damage decreases Klotho expression in kidneys from ApoE knockout mice. PLoS One 2013; 8:e83713.
11. Anagnostis P, Adamidou F, Slavakis A, Polyzos SA, Selalmatzidou D, Panagiotou A, et al. Comparative effect of atorvastatin and rosuvastatin on 25-hydroxy-vitamin D levels in non-diabetic patients with dyslipidaemia: a prospective randomized open-label pilot study. Open Cardiovasc Med J 2014; 8:55-60.
12. Girardi JM, Farias RE, Ferreira AP, Raposo NRB. Rosuvastatin prevents proteinuria and renal inflammation in nitric oxide-deficient rats. Clinics 2011; 66:1457-1462.
13. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 2005; 19:117-125.
14. Arshad AR. Comparison of low-dose rosuvastatin with atorvastatin in lipid-lowering efficacy and safety in a high-risk pakistani cohort: an open-label randomized trial. J Lipids 2014; 2014.
15. Kim MC, Ahn Y, Jang SY, Cho KH, Hwang SH, Lee MG, et al. Comparison of clinical outcomes of hydrophilic and lipophilic statins in patients with acute myocardial infarction. Korean J Intern Med 2011; 26:294-303.
16. Večeřa R, Zachařová A, Šiller M, Matušková Z, Škottová N, Anzenbacherová E, et al. The influence of rosuvastatin on liver microsomal CYP2C6 in hereditary hypertriglyceridemic rat. Neuro Endocrinol Lett 2012; 33:101-105.
17. Nurkalem Z, Yildirimtürk Ö, Özcan KS, Kul Ş, Çanga Y, Satılmış S, et al. The effect of rosuvastatin and atorvastatin on erectile dysfunction in hypercholesterolaemic patients. Kardiol Pol 2014; 72:275-279.
18. Fellström B, Zannad F, Schmieder R, Holdaas H, Jardine A, Rose H, et al. Effect of rosuvastatin on outcomes in chronic haemodialysis patients–design and rationale of the AURORA study. Curr Control Trials Cardiovasc Med 2005; 6:9.
19. Chan C. Hyperlipidaemia in chronic kidney disease. Ann. Acad. Med. Singap. 2005; 34:31-35.
20. Park J-S, Kim Y-J, Choi J-Y, Kim Y-N, Hong T-J, Kim D-S, et al. Comparative study of low doses of rosuvastatin and atorvastatin on lipid and glycemic control in patients with metabolic syndrome and hypercholesterolemia. Korean J Intern Med 2010; 25:27-35.
21. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003; 92:152-160.
22. Schulpis K, Karikas GA. Serum cholesterol and triglyceride distribution in 7767 school-aged Greek children. Pediatrics 1998; 101:861-864.
23. Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Cuccurullo F. Reaction conditions affecting the relationship between thiobarbituric acid reactivity and lipid peroxidesin human plasma. Free Radic Biol Med 2001; 31:331-335.
24. Reisin E, Liao J, Lee BS, Larroque M, Aguilar EA, Morse SA, et al. Effect of the HMG-CoA reductase inhibitor rosuvastatin on early chronic kidney injury in obese zucker rats fed with an atherogenic diet. Am J Med Sci 2009; 338:301-309.
25. Abrass CK. Cellular lipid metabolism and the role of lipids in progressive renal disease. Am J Nephrol 2004; 24:46-53.
26. van Himbergen TM, Matthan NR, Resteghini NA, Otokozawa S, Ai M, Stein EA, et al. Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers J Lipid Res 2009; 50:730-739.
27. Crevar-Sakač M, Vujić Z, Kotur-Stevuljević J, Ivanišević J, Jelić-Ivanović Z, Milenković M, et al. Effects of atorvastatin and artichoke leaf tincture on oxidative stress in hypercholesterolemic rats. Vojnosanit Pregl 2016; 73:178-187.
28. Agarwal R, editor Effects of statins on renal function. Mayo Clin. Proc 2007: Elsevier.
29.Xilifu D, Abudula A, Rehemu N, Zhao L, Zhou X, Zhang X. Effect of rosuvastatin on hyperuricemic rats and the protective effect on endothelial dysfunction. Exp Ther Med 2014; 8:1683-1688.
30. Kilit C, Koçak FE, Kilit TP. Comparison of the effects of high-dose atorvastatin and high-dose rosuvastatin on oxidative stress in patients with acute myocardial infarction: A pilot study. Turk Kardiyol Dern Ars 2017; 45:235-243.
31. Nishikido T, Oyama J-i, Keida T, Ohira H, Node K. High-dose statin therapy with rosuvastatin reduces small dense LDL and MDA-LDL: the standard versus high-dose therApy with Rosuvastatin for lipiD lowering (SARD) trial. J Cardiol 2016; 67:340-346.
32. Shehata AM, Yousef OM. Physiological studies on the risk factors responsible for atherosclerosis in rats. Nat and Sci 2010; 8:144-151.
33. Samani KG, Farrokhi E. Effects of cumin extract on oxLDL, paraoxanase 1 activity, FBS, total cholesterol, triglycerides, HDL-C, LDL-C, Apo A1, and Apo B in the patients with hypercholesterolemia. Int J Health Sci  2014; 8:39-43.
34. Beltowski J. Statins and modulation of oxidative stress. Toxicol. Mech. Methods 2005; 15:61-92.
35. Kasiske BL, O’Donnell MP, Schmitz PG, Kim Y, Keane WF, Daniels F, et al. Renal injury of diet-induced hypercholesterolemia in rats. Kidney Int. 1990; 37:880-891.
36. Selim ME, Yousef OM, Hamid SH, Aleisa NA. Hyperlipidemia aggravated renal disease in bacteremic male albino rats. J Med Sci 2013 ; 1:9-22.
37. Deng J, Wu G, Yang C, Li Y, Jing Q, Han Y. Rosuvastatin attenuates contrast-induced nephropathy through modulation of nitric oxide, inflammatory responses, oxidative stress and apoptosis in diabetic male rats. J Transl Med 2015; 13:53.
38. Li D, Chen H, Romeo F, Sawamura T, Saldeen T, Mehta JL. Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: role of LOX-1. J Pharmacol Exp Ther 2002; 302:601-605.
39. Yilmaz MI, Baykal Y, Kilic M, Sonmez A, Bulucu F, Aydin A, et al. Effects of statins on oxidative stress. Biol Trace Elem Res 2004; 98:119-127.
40. Panonnummal R, Yarkey J, Dinoop D. Are statins nephroprotective?: a dose dependent study in albino rats. Int J Pharm Pharm Sci 2013; 5:182-190.
41. Adekunle A, Adedeji A, Oyewo E, Adedosu O, Omotoso A. Hyperlipidemia induced by atherogenic diet enhanced oxidative stress in the kidney and inflammatory responses: an in vivo study. Asian J Nat Appl Sci 2013; 2:82-93.
42. Matos SL, Paula Hd, Pedrosa ML, Santos RCd, Oliveira ELd, Chianca Júnior DA, et al. Dietary models for inducing hypercholesterolemia in rats. Braz Arch Biol Techn 2005; 48:203-209.
43. Srinivas M, Annapurna A, Reddy YN. Anti-atherosclerotic effect of atorvastatin and clopidogrel alone and in combination in rats. Indian J Exp Biol 2008; 46:698-703.