Document Type : Original Article

Authors

1 Qaen School of Nursing and Midwifery, Birjand University of Medical Sciences, Birjand, Iran & Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran

2 Departments of Epidemiology and Biostatistics, School of Health Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran

3 Department of Biochemistry, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran

4 Department of Biochemistry, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran & Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran

Abstract

Background: Diabetic nephropathy (DN) is the most common cause of the end-stage renal disease (ESRD) globally. This study aimed to evaluate the effect of Crocin and Losartan on DN in diabetic rats.
Methods: A single dose of Streptozotocin (50 mg/kg IP) was administered to 40 male Wistar rats to induce diabetes. Crocin and Losartan (50 and 25 mg/kg, respectively) were given orally for four weeks. The study groups were untreated control, Diabetes, Crocin, Losartan, and Losartan-Crocin. At the end of the intervention, blood was tested for FBS, urea, UA, Cr, albumin, TG, TC, LDL-C, HDL-C, TAC, and MDA.
Results: Serum levels of FBS, urea, UA, TG, TC, and LDL-C increased significantly in the diabetic group compared to the untreated control group (P = 0.001), while albumin and HDL-C decreased significantly (P = 0.001). In the Crocin group, serum FBS, urea, TG, TC, and LDL-C levels were significantly lower than the diabetic group (P = 0.001), while serum albumin levels were significantly higher (P = 0.02). Serum levels of TAC and MDA in the Losartan group increased (P=0.04) and decreased significantly (P = 0.001) compared to the diabetic group, respectively.
Conclusion: The findings of the present study showed that Crocin could control hyperglycemia and prevent DN progression. It appears that combining Losartan with sufficient doses of Crocin improves its efficacy. However, understanding the exact mechanism of these changes requires further studies.

Keywords

  1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th Diabetes Res Clin Pract. 2019; 157:107843. doi: 10.1016/j.diabres.2019.107843.
  2. Baek JH, Lee WJ, Lee BW, Kim SK, Kim G, Jin SM, et al. Age at diagnosis and the risk of diabetic nephropathy in young patients with type 1 diabetes mellitus. Diabetes Metab J. 2021; 45(1):46-54. doi: 10.4093/dmj.2019.0134. 
  3. Sagoo MK, Gnudi L. Diabetic nephropathy: An overview. Methods Mol Biol. 2020; 2067:3-7. doi: 10.1007/978-1-4939-9841-8_1.
  4. Papadopoulou-Marketou N, Paschou SA, Marketos N, Adamidi S, Adamidis S, Kanaka-Gantenbein  Diabetic nephropathy in type 1 diabetes. Minerva Med. 2018; 109(3):218-28. doi: 10.23736/S0026-4806.17.05496-9.
  5. Zhang L, Wen Z, Han L, Zheng Y, Wei Y, Wang X, et al. Research progress on the pathological mechanisms of podocytes in diabetic nephropathy. J Diabetes Res. 2020; 7504798. doi: 10.1155/2020/7504798.
  6. Rianto F, Hoang T, Revoori R, Sparks MA. Angiotensin receptors in the kidney and vasculature in hypertension and kidney disease. Mol Cell Endocrinol. 2021; 529:111259. doi: 10.1016/j.mce.2021.111259.
  7. Koszegi S, Molnar A, Lenart L, Hodrea J, Balogh DB, Lakat T, et al. RAAS inhibitors directly reduce diabetes-induced renal fibrosis via growth factor inhibition.  J Physiol. 2019; 597(1):193-209. doi: 10.1113/JP277002.
  8. Pechlivanova D, Krumova E, Kostadinova N, Mitreva-Staleva J, Grozdanov P, Stoynev A. Protective effects of losartan on some type 2 diabetes mellitus-induced complications in Wistar and spontaneously hypertensive rats. Metab Brain Dis. 2020; 35(3):527-38. doi: 10.1007/s11011-020-00534-1.
  9. Hussain MA, Abogresha NM, AbdelKader G, Hassan R, Abdelaziz EZ, Greish SM. Antioxidant and anti-inflammatory effects of crocin ameliorate doxorubicin-induced nephrotoxicity in rats. Oxid Med Cell Longev. 2021; 2021:8841726. doi: 10.1155/2021/8841726.
  10. Elsherbiny NM, El-Sherbiny M, Said E. Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib. J Physiol Biochem. 2015; 71(4):635-48. doi: 10.1007/s13105-015-0428-6.
  11. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Analytical biochemistry. 1996; 239(1):70-6. doi: 10.1006/abio.1996.0292.
  12. Asri-Rezaei S, Tamaddonfard E, Ghasemsoltani-Momtaz B, Erfanparast A, Gholamalipour S. Effects of crocin and zinc chloride on blood levels of zinc and metabolic and oxidative parameters in streptozotocin-induced diabetic rats. Avicenna J Phytomed. 2015; 5(5):403-12. PMID: 26468459.
  13. Samarghandian S, Azimi-Nezhad M, Borji A, Farkhondeh T. Effect of crocin on aged rat kidney through inhibition of oxidative stress and proinflammatory state. Phytother Res. 2016; 30(8):1345-53. doi: 10.1002/ptr.5638.
  14. Kang C, Lee H, Jung ES, Seyedian R, Jo M, Kim J, et al. Saffron (Crocus sativus L.) increases glucose uptake and insulin sensitivity in muscle cells via multipathway mechanisms.  Food Chem. 2012; 135(4):2350-8. doi: 10.1016/j.foodchem.2012.06.092.
  15. Sefidgar SM, Ahmadi-Hamedani M, Jebelli Javan A, Narenji Sani R, Javaheri Vayghan A. Effect of crocin on biochemical parameters, oxidative/antioxidative profiles, sperm characteristics and testicular histopathology in streptozotocin-induced diabetic rats. Avicenna J Phytomed. 2019; 9(4):347-61. PMID: 31309073.
  16. Talebanzadeh S, Ashrafi M, Kazemipour N, Erjaee H, Nazifi S. Evaluation of the effects of saffron aqueous extract on oxidative stress in the lens of streptozotocin-induced diabetic rats. Biomedical Research and Therapy. 2018; 5(4):2133-41. doi:15419/bmrat.v5i4.427.
  17. Yaribeygi H, Noroozadeh A, Taghi-Mohammadi M, Johnston TP, Sahebkar AH. Crocin improves oxidative stress by potentiating intrinsic Anti-Oxidant defense systems in pancreatic cells during uncontrolled hyperglycemia. Pharmacopuncture. 2019; 22(2):83-9. doi: 10.3831/KPI.2019.22.010.
  18. Michishita R, Matsuda T, Kawakami S, Tanaka S, Kiyonaga A, Tanaka H, et al. Hypertension and hyperglycemia and the combination thereof enhances the incidence of chronic kidney disease (CKD) in middle-aged and older males. Clin Exp Hypertens. 2017; 39(7):645-54. doi: 10.1080/10641963.2017.1306541.
  19. Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. Chem Biol Interact. 2018; 284:90-100. doi: 10.1016/j.cbi.2018.02.001.
  20. Lee YJ, Cho S, Kim SR, Jang HR, Lee JE, Huh W, et al. Effect of losartan on proteinuria and urinary angiotensinogen excretion in non-diabetic patients with chronic kidney disease. Postgrad Med J. 2011; 87(1032):664-9. doi: 10.1136/pgmj.2011.118059.
  21. El-Fawal R, El Fayoumi HM, Mahmoud MF. Diosmin and crocin alleviate nephropathy in metabolic syndrome rat model: Effect on oxidative stress and low grade inflammation. Biomed Pharmacother 2018; 102:930-7. doi: 10.1016/j.biopha.2018.03.162.
  22. Amin SN, El-Gamal EM, Rashed LA, Kamar SS, Haroun MA. Inhibition of notch signalling and mesangial expansion by combined glucagon like peptide-1 agonist and crocin therapy in animal model of diabetic nephropathy. Arch Physiol Biochem. 2020: 1-11. doi: 10.1080/13813455.2020.1846203.
  23. Altinoz E, Oner Z, Elbe H, Cigremis Y, Turkoz Y. Protective effects of saffron (its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Hum Exp Toxicol. 2015; 34(2):127-34. doi: 10.1177/0960327114538989.
  24. Yaribeygi H, Mohammadi MT, Rezaee R, Sahebkar AH. Crocin improves renal function by declining Nox-4, IL-18, and p53 expression levels in an experimental model of diabetic nephropathy. J Cell Biochem. 2018; 119(7):6080-93. doi: 10.1002/jcb.26806.
  25. Chang DC, Xu X, Ferrante-Jr AW, Krakoff J. Reduced plasma albumin predicts type 2 diabetes and is associated with greater adipose tissue macrophage content and activation. Diabetol Metab Syndr. 2019; 11(1):14. doi: 10.1186/s13098-019-0409-y.
  26. Zhang J, Zhang R, Wang Y, Li H, Han Q, Wu Y, et al. The level of serum albumin is associated with renal prognosis in patients with diabetic nephropathy. J Diabetes Res. 2019; 2019:7825804. doi: 10.1155/2019/7825804.
  27. Iwasaki T, Togashi Y, Terauchi Y. Significant association of serum albumin with severity of retinopathy and neuropathy, in addition to that of nephropathy, in Japanese type 2 diabetic patients. Endocr J. 2008; 55(2):311-6. doi: 10.1507/endocrj.k07-086.
  28. Nandini HS, Naik PR. Action of corilagin on hyperglycemia, hyperlipidemia and oxidative stress in streptozotocin-induced diabetic rats. Chem Biol Interact. 2019; 299:186-93. doi: 10.1016/j.cbi.2018.12.012.
  29. Naserizadeh SK, Taherifard MH, Shekari M, Mesrkanlou HA, Asbaghi O, Nazarian B, et al. The effect of crocin supplementation on lipid concentrations and fasting blood glucose: A systematic review and meta-analysis and meta-regression of randomized controlled trials. Complement Ther Med. 2020; 52:102500. doi: 10.1016/j.ctim.2020.102500.
  30. Fajriana H, Farmawati A, Arsanti-Lestari L. Antioxidant effect of purple eggplant flour (solanum melongena l.) against oxidative stress in hyperglycaemic rats. Romanian Journal of Diabetes Nutrition and Metabolic Diseases. 2017; 24(3):247-54. doi:1515/rjdnmd-2017-0030.
  31. Nair AR, Ebenezer PJ, Saini Y, Francis J. Angiotensin II-induced hypertensive renal inflammation is mediated through HMGB1-TLR4 signaling in rat tubulo-epithelial cells. Exp Cell Res. 2015; 335(2):238-47. doi: 10.1016/j.yexcr.2015.05.011. 
  32. Shirai A, Yamazaki O, Horita S, Nakamura M, Satoh N, Yamada H, et al. Angiotensin II dose-dependently stimulates human renal proximal tubule transport by the nitric oxide/guanosine 3',5'-cyclic monophosphate pathway. J Am Soc Nephrol. 2014; 25(7):1523-32. doi: 10.1681/ASN.2013060596.
  33. Ateyya H, Nader MA, El-Sherbeeny NA. Beneficial effects of rosiglitazone and losartan combination in diabetic rats. Can J Physiol Pharmacol. 2018; 96(3):215-20. doi: 10.1139/cjpp-2017-0332.