Evaluation of PPAR-α Agonist effect on Kidney Performance Through Increment of Nitric Oxide During Hyperglycemia-Induced Nephropathy in Rat


Department of Physiology and Biophysics, School of Medicine, Baqiyatallah University of Medical Sciences, Tehran, IR Iran


Background: Chronic uncontrolled hyperglycemia is the common reason of renal failure.
Objectives: We aimed to assess the possible protective effects of PPAR-α agonist (fenofibrate) on kidney performance and nitric oxide (NO) level of kidney in experimental model of diabetic nephropathy (DN).
Materials and Methods: Male Wistar rats were randomly divided into four groups (n = 6); Normal, Normal treatment, Diabetic and Diabetic treatment. Rats were made diabetic by an intravenous injection of streptozotocin (40 mg/kg). After 72 hours, blood samples were collected for approving diabetes and the rats with blood glucose above 400 mg/dL were considered as diabetic animals. Treated
groups received orally fenofibrate for 8 weeks (80 mg/kg/day). At the end, blood samples were collected for measuring blood glucose
and creatinine. Finally, NO content and histopathological assessments of kidney were assessed at termination of experiment.
Results: Fenofibrate did not change the blood glucose of normal or diabetic rats. Diabetes increased the proteinuria (82%) and blood creatinine of diabetic rats (4.51 ± 0.45 mg/dL) compared to normal rats (0.66 ± 0.14 mg/dL). Chronic hyperglycemia also decreased
the content of renal NO (37%) compared with normal rats in accompany with histopathological damages. Fenofibrate significantly decreased the proteinuria (80%) and blood creatinine of diabetic rats (1.66±0.23 mg/dL). The content of NO increased in the kidney
of both treated rats (31%). Fenofibrate also improved the histopathological changes of diabetic kidney.
Conclusions: Our findings indicate that fenofibrate (PPAR-αagonist) is able to prevent DN progression and improve kidney performance during chronic uncontrolled hyperglycemia possibly through increase in NO bioavailability of kidney


1.Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, GarciaPerez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7(6):327–40. doi:10.1038/nrneph.2011.51. [PubMed: 21537349].
2. Fraser DJ, Phillips AO. Diabetic nephropathy. Medicine.2007;35(9):503–6. doi: 10.1016/j.mpmed.2007.06.007.
3. Tavafi M. Diabetic nephropathy and antioxidants. J Nephropathol. 2013;2(1):20–7. doi: 10.5812/nephropathol.9093. [PubMed: 24475422].
4. Jerums G, Premaratne E, Panagiotopoulos S, Clarke S, Power DA, MacIsaac RJ. New and old markers of progression of diabeticnephropathy. Diabetes Res Clin Pract. 2008;82 Suppl 1:S30–7. doi:10.1016/j.diabres.2008.09.032. [PubMed: 18937992].
5. Arora MK, Singh UK. Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update. Vascul Pharmacol. 2013;58(4):259–71. doi: 10.1016/j.vph.2013.01.001. [PubMed: 23313806].
6. Veelken R, Hilgers KF, Hartner A, Haas A, Bohmer KP, Sterzel RB. Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol. 2000;11(1):71–9. [PubMed:
7. Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, CampbellThompson M, et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc
Nephrol. 2007;18(2):539–50. doi: 10.1681/ASN.2006050459. [PubMed:17202420].
8. Brodsky SV, Gao S, Li H, Goligorsky MS. Hyperglycemic switch from mitochondrial nitric oxide to superoxide production in endothelial cells. Am J Physiol Heart Circ Physiol. 2002;283(5):H2130–9. doi10.1152/ajpheart.00196.2002. [PubMed: 12384491].
9. Da Silva-Azevedo L, Baum O, Zakrzewicz A, Pries AR. Vascular endothelial growth factor is expressed in endothelial cells isolated from skeletal muscles of nitric oxide synthase knockout mice during prazosin-induced angiogenesis. Biochem Biophys Res Commun. 2002;297(5):1270–6. [PubMed: 12372425].
10. Kang DH, Nakagawa T, Feng L, Johnson RJ. Nitric oxide modulates vascular disease in the remnant kidney model. Am J Pathol.2002;161(1):239–48. doi: 10.1016/S0002-9440(10)64175-2. [PubMed:
11. Zhao Q, Egashira K, Inoue S, Usui M, Kitamoto S, Ni W, et al. Vascular endothelial growth factor is necessary in the development of arteriosclerosis by recruiting/activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis. Circulation.2002;105(9):1110–5. [PubMed: 11877364].
12. Cheng H, Wang H, Fan X, Paueksakon P, Harris RC. Improvement of endothelial nitric oxide synthase activity retards the progression of diabetic nephropathy in db/db mice. Kidney Int. 2012;82(11):1176–83. doi:10.1038/ki.2012.248. [PubMed: 22785174].
13. Kostapanos MS, Florentin M, Elisaf MS. Fenofibrate and the kidney: an overview. Eur J Clin Invest. 2013;43(5):522–31. doi: 10.1111/eci.12068.[PubMed: 23480615].
14. Park CW, Kim HW, Ko SH, Chung HW, Lim SW, Yang CW, et al. Accelerated diabetic nephropathy in mice lacking the peroxisomeproliferator-activated receptor alpha. Diabetes. 2006;55(4):885–93. [PubMed: 16567507].
15. Li L, Emmett N, Mann D, Zhao X. Fenofibrate attenuates tubulointerstitial fibrosis and inflammation through suppression of nuclear factor-kappaB and transforming growth factor-beta1/Smad3 in diabetic nephropathy. Exp Biol Med (Maywood). 2010;235(3):383–91. doi: 10.1258/ebm.2009.009218. [PubMed: 20404057].
16. Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 2006;212(2):167–78. doi: 10.1016/j.taap.2006.01.003. [PubMed:16490224].
17. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal Biochem. 1976;72:248–54. [PubMed: 942051].
18. Baylis C. Nitric oxide deficiency in chronic kidney disease. Am J Physiol Renal Physiol. 2008;294(1):F1–9. doi: 10.1152/ajprenal.00424.2007. [PubMed: 17928410].
19. Perrone RD, Madias NE, Levey AS. Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem. 1992;38(10):1933–53. [PubMed: 1394976].
20. Ruggenenti P, Gaspari F, Perna A, Remuzzi G. Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes. BMJ. 1998;316(7130):504–9. [PubMed: 9501711].
21. Warram JH, Gearin G, Laffel L, Krolewski AS. Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. J Am Soc Nephrol. 1996;7(6):930–7. [PubMed: 8793803].
22. Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care. 1999;22(8):1245–51. [PubMed: 10480765].
23. 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(1-2):149–62. doi: 10.1007/s11010-008-9917-z. [PubMed: 18830571].
24. Chen L, Zhang J, Zhang Y, Wang Y, Wang B. Improvement of inflammatory responses associated with NF-kappa B pathway in kidneys from diabetic rats. Inflamm Res. 2008;57(5):199–204. doi: 10.1007/s00011-
006-6190-z. [PubMed: 18465086].
25. Rosenson RS, Wolff DA, Huskin AL, Helenowski IB, Rademaker AW. Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects
with hypertriglyceridemia and the metabolic syndrome. Diabetes Care. 2007;30(8):1945–51. doi: 10.2337/dc07-0015. [PubMed: 17483155].
26. Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem. 2001;276(32):30392–8. doi: 10.1074/jbc.M103702200. [PubMed: 11402048].
27. Goya K, Sumitani S, Xu X, Kitamura T, Yamamoto H, Kurebayashi S, et al. Peroxisome proliferator-activated receptor alpha agonists
6 Razavi Int J Med. 2016; 4(2):e37670. Yaribeygi H and Mohammadi MT increase nitric oxide synthase expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24(4):658–63. doi: 10.1161/01.ATV.0000118682.58708.78. [PubMed: 14751809].