EFFECT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA-AGONISTS ON DIABETES-INDUCED ACUTE KIDNEY INJURY: ROLE OF OXIDATIVE STRESS AND HYPERLIPIDEMIA
Objective: The present study investigated the possible effect of fenofibrate and gemfibrozil peroxisome proliferator-activated receptor-alpha agonist in diabetes-induced acute kidney injury (AKI) in rats.
Methods: Rats were administered streptozotocin (STZ) (50 mg/kg, i.p., single dose) to induce experimental diabetes mellitus. The development of diabetic AKI was assessed biochemically and histologically. In addition, the diabetes-induced lipid profile and renal oxidative stress were assessed. The single dose of STZ produced diabetes, which induced renal oxidative stress, altered the lipid profile and subsequently produced kidney injuryAKI in 7 weeks by increasing serum creatinine, blood urea nitrogen (BUN), proteinuria, and glomerular damage. Treatment with fenofibrate and gemfibrozil (30 mg/kg p.o, 7 weeks) normalized the altered lipid profile by decreasing serum cholesterol, triglycerides, and increasing serum high-density lipoprotein in diabetic rats. Lisinopril (1 mg/kg, p.o., 7 weeks, reference compound) prevents lipid alteration and development of diabetic AKI.
Result: Fenofibrate and gemfibrozil, besides hyperglycemia, significantly prevented the development of diabetic AKI by reducing (serum and tissue) oxidative stress, hyperlipidemia, serum BUN, creatinine, and urinary protein. Further, fenofibrate, but not gemfibrozil, considerably reduced renal structural and functional abnormalities in diabetic rats. The fenofibrate was more effective in attenuating the diabetes-induced AKI and renal oxidative stress as compared to treatment with and gemfibrozil.
Conclusion: The fenofibrate and gemfibrozil treatment markedly prevented the diabetes-induced AKI. In comparison, the fenofibrate is found to be a superior approach to attenuate the diabetic AKI than gemfibrozil.
2. Star RA. Treatment of acute renal failure. Kidney Int 1998;54:1817-31.
3. Sharma D, Bhattacharya P, Kalia K, Tiwari V. Diabetic nephropathy: New insights into established therapeutic paradigms and novel molecular targets. Diabetes Res Clin Pract 2017;128:91-108.
4. Sharina IG, Sobolevsky M, Papakyriakou A, Rukoyatkina N, Spyroulias GA, Gambaryan S, et al. The fibrate gemfibrozil is a NO- and haem-independent activator of soluble guanylyl cyclase: In vitro studies. Br J Pharmacol 2015;172:2316-29.
5. Balakumar P, Chakkarwar VA, Singh M. Ameliorative effect of combination of benfotiamine and fenofibrate in diabetes-induced vascular endothelial dysfunction and nephropathy in the rat. Mol Cell Biochem 2009;320:149-62.
6. Balakumar P, Varatharajan R, Nyo YH, Renushia R, Raaginey D, Oh AN, et al. Fenofibrate and dipyridamole treatments in low-doses either alone or in combination blunted the development of nephropathy in diabetic rats. Pharmacol Res 2014;90:36-47.
7. Kadian S, Mahadevan N, Balakumar P. Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy. Eur J Pharmacol 2013;698:388-96.
8. Dhodi JB, Mestry SN, Juvekar AR. Diabetic nephropathy-genesis, prevention, and treatment. Int J Pharm Pharm Sci 2014;6:42-7.
9. Hu C, Sun L, Xiao L, Han Y, Fu X, Xiong X, et al. Insights into the mechanisms involved in the expression and regulation of extracellular matrix proteins in diabetic nephropathy. Curr Med Chem 2015;22:2858 70.
10. Fioretto P, Mauer M. Histopathology of diabetic nephropathy. Semin Nephrol 2007;27:195-207.
11. Senthilkumar N, Anandhasayanam A, Safil KM, Shemimol S. A comparative study on the effectiveness of angiotensin converting enzyme inhibitors (ACEIS) and angiotensin receptor blockers (ARBS) in diabetic nephropathy in Type 2 diabetes mellitus patients. Int J Pharm Pharm Sci 2016;8:289-92.
12. Zhao HJ, Wang S, Cheng H, Zhang MZ, Takahashi T, Fogo AB, et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 2006;17:2664-9.
13. Hayashi D, Ueda S, Yamanoue M, Ashida H, Shirai Y. Amelioration of diabetic nephropathy by oral administration of d-Î±-tocopherol and its mechanisms. Biosci Biotechnol Biochem 2018;82:65-73.
14. Arora MK, Singh UK. Molecular mechanisms in the pathogenesis of diabetic nephropathy: An update. Vascul Pharmacol 2013;58:259 71.
15. Palm F. Intrarenal oxygen in diabetes and a possible link to diabetic nephropathy. Clin Exp Pharmacol Physiol 2006;33:997-1001.
16. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res 1994;74:1141-8.
17. Balakumar P, Chakkarwar VA, Krishan P, Singh M. Vascular endothelial dysfunction: A tug of war in diabetic nephropathy? Biomed Pharmacother 2009;63:171-9.
18. Wolf G, Ziyadeh FN. Cellular and molecular mechanisms of proteinuria in diabetic nephropathy. Nephron Physiol 2007;106:26 31.
19. Taskinen MR. 3 hyperlipidaemia in diabetes. Baillieres Clin Endocrinol Metab 1990;4:743-75.
20. Figarola JL, Loera S, Weng Y, Shanmugam N, Natarajan R, Rahbar S, et al. LR-90 prevents dyslipidaemia and diabetic nephropathy in the zucker diabetic fatty rat. Diabetologia 2008;51:882-91.
21. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470 5.
22. Park CW, Kim HW, Ko SH, Chung HW, Lim SW, Yang CW, et al. Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha. Diabetes 2006;55:885-93.
23. Ali MM, Agha FG. Amelioration of streptozotocin-induced diabetes mellitus, oxidative stress and dyslipidemia in rats by tomato extract lycopene. Scand J Clin Lab Invest 2009;69:371-9.
24. Kang HW, Lim WC, Lee JK, Ho JN, Lim EJ, Cho HY, et al. Germinated waxy black rice ameliorates hyperglycemia and dyslipidemia in streptozotocin-induced diabetic rats. Biol Pharm Bull 2017;40:1846 55.
25. Sevak AR, Goyal RK. Effects of chronic treatment with lisinopril on cardiovascular complications in streptozotocin diabetic and DOCA hypertensive rats. Pharmacol Res 1996;34:201-9.
26. Trevisan R, Dodesini AR, Lepore G. Lipids and renal disease. J Am Soc Nephrol 2006;17 4 suppl 2:S145-7.
27. Vaziri ND, Sato T, Liang K. Molecular mechanism of altered cholesterol metabolism in focal glomerulosclerosis. Kidney Int 2003;63:1756-63.
28. Amann B, Tinzmann R, Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care 2003;26:2421-5.