• Putu Nita Cahyawati 1Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Ngatidjan . Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Dwi Cahyani Ratna Sari Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Muhammad Mansyur Romi Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Nur Arfian Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Muhammad Mansyur Romi Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Muhammad Mansyur Romi Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Nur Arfian Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
  • Nur Arfian Department of Anatomy, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia


Objective: The objective of this study to investigate the effect of simvastatin on kidney fibrosis in mice with a 5/6 subtotal nephrectomy.

Methods: Thirty adults (3 mo old) male Swiss mice were submitted to a 5/6 subtotal nephrectomy and studied after 14 d. Animals were divided into five groups: 5/6 subtotal nephrectomy (SN, n=6), sham operation (SH, n=6), simvastatin 5.2 mg/kg body weight (SIM-1, n=6), simvastatin 10.4 mg/kg body weight (SIM-2, n=6), and simvastatin 20.8 mg/kg body weight (SIM-3, n=6) groups. At sacrifice, kidneys were harvested for morphology (glomerulosclerosis (GS), tubular injury and interstitial fibrosis), immunostaining (α-smooth muscle actin (α-SMA)) and platelet-derived growth factor receptor beta (PDGF-Rβ) and reverse transcriptase-polymerase chain reaction (RT-PCR) (MCP-1, ICAM-1, nephrin, and podocin) analysis.

Results: Glomerulosclerosis, tubular injury and interstitial fibrosis in the simvastatin group was significantly lower than SN group (p<0.05). Simvastatin significantly reduced α-SMA expression (3.61±1.06 vs 7.91±1.26, p<0.05, SIM-1 vs SN; 2.86±0.61 vs 7.91±1.26, p<0.05, SIM-2 vs SN; 1.71±0.50 vs 7.91±1.26, p<0.05, SIM-3 vs SN), MCP-1 was markedly expressed in the 5/6 subtotal nephrectomy kidneys and was reduced with simvastatin (1.4±0.64 vs 0.57±0.23, p<0.05, SN vs SIM-1; 1.4±0.64 vs 0.6±0.26, p<0.05, SN vs SIM-2; 1.4±0.64 vs 0.52±0.21, SN vs SIM-3, p<0.05). Simvastatin did not increase nephrin expression, but it increased podocin expression significantly in the SIM-3 group.

Conclusion: Simvastatin significantly attenuated GS, tubular injury and interstitial fibrosis through the downregulation of myofibroblast expansion and inflammatory mediators in mice with a 5/6 subtotal nephrectomy.

Keywords: Simvastatin, Kidney fibrosis, Inflammatory mediator, Myofibroblast, Subtotal nephrectomy


Download data is not yet available.


1. Hamasaki Y, Doi K, Okamoto K, Ijichi H, Seki G, Maeda-Mamiya R, et al. 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13–USAG-1 pathway. Laboratory Investigation 2012;92:1161–70.
2. Lopez-Novoa JM, Martinez-Salgado C, Rodriguez-Pena AB, Hernandez FJL. Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives. Pharmacol Ther 2010;128:61–81.
3. Babelova A, Jansen F, Sander K, Lohn M, Schafer L, Fork, C, et al. Activation of rac-1 and rhoA contributes to podocyte injury in chronic kidney disease. Plos One 2013;8:e80328.
4. Sheng X, Murphy MJ, Macdonald TM, Wei L. Effectiveness of statins in chronic kidney disease. Q J Med 2012;105:641–8.
5. Laufs U, Liao JK. Isoprenoid metabolism and the pleiotropic effects of statins. Curr Atheroscler Rep 2003;5:372–8.
6. Tristano AG, Fuller K. Immunomodulatory effects of statins and autoimmune rheumatic diseases: novel intracellular mechanism involved. Int J Immunopharmacol 2006;6:1833–46.
7. Wei P, Grimm PR, Settles DC, Balwanz CR, Padanilam BJ, Sansom SC. Simvastatin reverses podocyte injury but not a mesangial expansion in early stage type 2 diabetes mellitus. Renal Failure 2009;31:503–13.
8. Diez RR, Rodrigues-Diez R, Lavoz C, Rayego-Mateos S, Civantos E, Rodriiguez-Vita J. Statins inhibit angiotensin II/smad pathway and related vascular fibrosis, by a TGF-b-independent process. Plos One 2010;5:e14145.
9. Toba H, Mitani T, Takahashi T, Imai N, Serizawa R, Wang J, et al. Inhibition of the renal renin-angiotensin system and renoprotection by pitavastatin in type 1 diabetes. Clin Exp Pharmacol Physiol 2010;37:1064–70.
10. Zhang W, Li Q, Wang LJ, Yang XQ. Simvastatin ameliorates glomerulosclerosis in adriamycin-induced-nephropathy rats. Pediatr Nephrol 2008;23:2185–94.
11. Zhou MS, Schuman IH, Jaimes EA, Raij L. Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-β, and fibronectin with a concomitant increase in nitric oxide bioavailability. Am J Physiol Renal Physiol 2008;295:F53–9.
12. Haynes R, Lewis D, Emberson J, Reith C, Agodoa L, Cass A, et al. Effects of lowering ldl cholesterol on the progression of kidney disease. J Am Soc Nephrol 2014;25.
13. Nikolic D, Banach M, Nikfar S, Salari P, Mikhailidis DP, Toth PP, et al. A meta-analysis of the role of statins on renal outcomes in patients with chronic kidney disease. Is the duration of therapy important?. Int J Cardiol 2013;168:5437-47.
14. Geng Q, Ren J, Song J, Li S, Chen H. Meta-analysis of the effect of statins on renal function. Am J Cardiol 2014;114:562-70.
15. Gava AL, Freitas FPS, Balarini CM, Vasquez EC, Meyrelles SS. Effects of 5/6 nephrectomy on renal function and blood pressure in mice. Int J Physiol Pathophysiol Pharmacol 2012;4:67-73.
16. Inui Y, Mochida H, Yamairi F, Okada M, Ishida J, Fukamizu A, et al. Effects of aging and uninephrectomy on renal changes in tsukuba hypertensive mice. Biomedical Reports 2013;1:359-64.
17. Nagasu H, Satoh M, Kidokoro K, Nishi Y, Channon KM, Sasaki T, et al. Endothelial dysfunction promotes the transition from compensatory renal hypertrophy to kidney injury after unilateral nephrectomy in mice. Am J Physiol Renal Physiol 2012;302:F1402–8.
18. Christensene M, Su AW, Snyder RW, Greco A, Lipschutz JH, Madaio MP. Simvastatin protection against acute immune-mediated glomerulonephritis in mice. Kidney Int 2006; 69:457–63.
19. Bae EH, Kim IJ, Park JW, Ma SK, Lee JU, Kim SW. Renoprotective effect of rosuvastatin in DOCA–hypertensive salt rats. Nephrol Dial Transplant 2010;25:1051–9.
20. Shibata S, Nagase M, Fujita T. Fluvastatin ameliorates podocyte injury in proteinuric rats via modulation of excessive rho signalling. J Am Soc Nephrol 2006;17:754–64.
21. Reddy VC, Amulya V, Lakshmi CHA, Reddy DBPK, Pratima D, Thirupathi AT, et al. Effect of simvastatin in gentamicin-induced nephrotoxicity in albino rats. Asian J Pharm Clin Res 2012;5:36-40.
22. Girardi JM, Farias RE, Ferreira AP, Raposo NRB. Rosuvastatin prevents proteinuria and renal inflammation in nitric oxide–deficient rats. Clinics 2011;66:1457-62.
23. Douglas K, O’Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med 2006;145:117-25.
24. Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003; 41:565–70.
25. Nitta K. Clinical assessment and management of dyslipidemia in patients with chronic kidney disease. Clin Exp Nephrol 2012;16:522–9.
26. Vieira JM, Mantovani E, Rodrigues LT, Delle H, Noronha IL, Fujihara CK, et al. Simvastatin attenuates renal inflammation, tubular transdifferentiation and interstitial fibrosis in rats with unilateral ureteral obstruction. Nephrol Dial Transplant 2005;20:1582–91.
27. Vieira JM, Rodrigues LT, Mantovani E, Delle H, Mattar AL, Malheiros DM, et al. Statin monotherapy attenuates renal injury in a salt-sensitive hypertension model of the renal disease. Nephron Physiol 2005;101:82-91.
28. Chade AR, Zhu XY, Grande JP, Krier JD, Lerman A, Lerman LO. Simvastatin abates development of renal fibrosis in experimental renovascular disease. J Hypertens 2008;26: 1651-60.
29. Yagi S, Aihara K, Ikeda Y, Sumitomo Y, Yoshida S, Ise T, et al. Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II–induced cardiovascular remodeling and renal insufficiency. Circ Res 2008;102:68-76.
30. Nachtigal P, Pospisilova N, Vecerova L, Micuda S, Brcakova E, Pospechova K, et al. Atorvastatin increases endoglin, SMAD2, phosphorylated SMAD2/3 and eNOS expression in ApoE/lDLR double knock out mice. J Atheroscler Thromb 2009;16:265-74.
31. Weng TC, Yang YH, Lin SJ, Tai SH. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther 2010;35:139-51.
32. Fogo AB. Mechanisms of progression of chronic kidney disease. Pediatr Nephrol 2007;22:2011–22.
33. Katz A, Caramori ML, Sisson-Ross S, Groppoli T, Basgen JM, Mauer M. An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients. Kidney Int 2002;61:2058–66.
34. Lin FL, Shen HC, Zhu B, Lin KQ. Effects of simvastatin on the expression of CTGF and α-SMA in renal tubulointerstitium of rats with diabetic nephropathy. J Zhejiang Univ 2010;39:511-6.
35. Campanholle G, Ligresti G, Gharib SA, Duffield JS. Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis. Am J Physiol Cell Physiol 2013;304:C591–603.
36. Nakagawa N, Duffield JS. Myofibroblasts in fibrotic kidneys. Curr Pathobiol Rep 2013;1:1-14.
37. Mun JH, Kim YM, Kim BS, Kim JH, Kim MB, Ko HC. Simvastatin inhibits transforming growth factor-β1-induced expression of type 1 collagen, CTGF, and α-SMA in keloid fibroblasts. Wound Rep Reg 2014;22:125–33.
38. Benton JA, Kern HB, Leinwand LA, Mariner PD, Anseth KS. Statins block calcific nodule formation of valvular interstitial cells by inhibiting α-smooth muscle actin expression. Arterioscler Thromb Vasc Biol 2009;29. Doi:10.1161/ atvbaha.109.195271
39. Porter KE, Turner NA, O’Regan DJ, Balmforth AJ, Ball SG. Simvastatin reduces human atrial myofibroblast proliferation independently of cholesterol lowering via inhibition of rhoA. Cardiovasc Res 2004;61:745–55.
40. Copaja M, Venegas D, Aranguiz P, Canales J, Vivar R, Avalos Y, et al. Simvastatin disrupts cytoskeleton and decreases cardiac fibroblast adhesion, migration and viability. Toxicology 2012;294:42–9.
41. Panonnummal R, Varkey J. Statin-induced nephrotoxicity: a dose dependent study in albino rats. Int J Pharm Sci 2014;6:401-6.
521 Views | 1393 Downloads
How to Cite
Cahyawati, P. N., N. ., D. C. R. Sari, M. M. Romi, N. Arfian, M. M. Romi, M. M. Romi, N. Arfian, and N. Arfian. “SIMVASTATIN ATTENUATES RENAL FAILURE IN MICE WITH A 5/6 SUBTOTAL NEPHRECTOMY”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 9, no. 5, May 2017, pp. 12-17, doi:10.22159/ijpps.2017v9i5.12261.
Original Article(s)