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The renoprotective effect of glycyrrhizic acid in insulin-resistant rats exposed to aluminum involves the inhibition of TLR4/NF-κB signaling pathway

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Abstract

Aluminum is well recognized as a nephrotoxic agent. Its hazardous effects arise from the high risk of daily exposure. The consumption of fructose also represents a critical health issue that might negatively impact different organs, including the kidneys. To pursue our previous work, this study aimed to investigate the potential renoprotective effects of glycyrrhizic acid (GLYA) on aluminum-induced nephrotoxicity in insulin-resistant rats. Insulin resistance (IR) was induced by adding fructose (10%) in drinking water for 18 weeks. Male Wistar rats were divided into five groups: control (CTRL), aluminum chloride (ALM, 34 mg/kg/day), fructose (FRCT), aluminum plus fructose (AL/FR), and GLYA (rats received AL/FR and treated with 40 mg/kg GLYA daily). AL/FR resulted in abnormal renal function tests and renal tissue injury. This was associated with increased oxidative stress and inflammation in the renal tissue. Moreover, the expressions of the toll-like receptor 4 (TLR4) and its adaptor proteins were increased in AL/FR group. The administration of GLYA mollified AL/FR-induced renal injury, oxidative stress, activation of the TLR4 signaling pathway, and inflammation. In conclusion, we provide evidence for the promising renoprotective effect of GLYA against AL/FR-induced kidney damage in rats. The renoprotection is attributed to the suppression of oxidative stress and inhibition of the TLR4/NF-κB signaling pathway in the kidneys.

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References

  • Abdel Moneim AE, Othman MS, Mohmoud SM, El-Deib KM (2013) Pomegranate peel attenuates aluminum-induced hepatorenal toxicity. Toxicol Mech Methods 23:624–633

    Article  CAS  PubMed  Google Scholar 

  • Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    Article  CAS  PubMed  Google Scholar 

  • Al Dera HS (2016) Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats. Saudi Med J 37:369–378

    Article  PubMed  PubMed Central  Google Scholar 

  • Al Kahtani MA, Abdel-Moneim AM, El-Sayed WM (2014) The influence of taurine pretreatment on aluminum chloride induced nephrotoxicity in Swiss albino mice. Histol Histopathol 29:45–55

    PubMed  Google Scholar 

  • Ali NM, Mahmoud AAA, Mahmoud MF, El Fayoumi HM (2019) Glycyrrhizic acid and silymarin alleviate the neurotoxic effects of aluminum in rats challenged with fructose-induced insulin resistance: possible role of toll-like receptor 4 pathway. Drug Chem Toxicol 42:210–219

    Article  CAS  PubMed  Google Scholar 

  • Aoyama M, Isshiki K, Kume S, Chin-Kanasaki M, Araki H, Araki S, Koya D, Haneda M, Kashiwagi A, Maegawa H, Uzu T (2012) Fructose induces tubulointerstitial injury in the kidney of mice. Biochem Biophys Res Commun 419:244–249

    Article  CAS  PubMed  Google Scholar 

  • Belaid-Nouira Y, Bakhta H, Haouas Z, Flehi-Slim I, Ben Cheikh H (2013) Fenugreek seeds reduce aluminum toxicity associated with renal failure in rats. Nutr Res Pract 7:466–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dharnidharka VR, Kwon C, Stevens G (2002) Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40:221–226

    Article  CAS  PubMed  Google Scholar 

  • El-Kenawy Ael M, Hussein Osman HE, Daghestani MH (2014) Role of propolis (bee glue) in improving histopathological changes of the kidney of rat treated with aluminum chloride. Environ Toxicol 29:1000–1010

    Article  Google Scholar 

  • Feng C, Wang H, Yao C, Zhang J, Tian Z (2007) Diammonium glycyrrhizinate, a component of traditional Chinese medicine Gan-Cao, prevents murine T-cell-mediated fulminant hepatitis in IL-10- and IL-6-dependent manners. Int Immunopharmacol 7:1292–1298

    Article  CAS  PubMed  Google Scholar 

  • Fiore C, Eisenhut M, Krausse R, Ragazzi E, Pellati D, Armanini D, Bielenberg J (2008) Antiviral effects of Glycyrrhiza species. Phytother Res 22:141–148

    Article  CAS  PubMed  Google Scholar 

  • Flaten TP (2001) Aluminium as a risk factor in Alzheimer’s disease, with emphasis on drinking water. Brain Res Bull 55:187–196

    Article  CAS  PubMed  Google Scholar 

  • Fujisawa Y, Sakamoto M, Matsushita M, Fujita T, Nishioka K (2000) Glycyrrhizin inhibits the lytic pathway of complement--possible mechanism of its anti-inflammatory effect on liver cells in viral hepatitis. Microbiol Immunol 44:799–804

    Article  CAS  PubMed  Google Scholar 

  • Gersch MS, Mu W, Cirillo P, Reungjui S, Zhang L, Roncal C, Sautin YY, Johnson RJ, Nakagawa T (2007) Fructose, but not dextrose, accelerates the progression of chronic kidney disease. Am J Physiol Ren Physiol 293:F1256–F1261

    Article  CAS  Google Scholar 

  • Gumpricht E, Dahl R, Devereaux MW, Sokol RJ (2005) Licorice compounds glycyrrhizin and 18beta-glycyrrhetinic acid are potent modulators of bile acid-induced cytotoxicity in rat hepatocytes. J Biol Chem 280:10556–10563

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Wang S, Wang Y, Zhu T (2016) Silymarin improved diet-induced liver damage and insulin resistance by decreasing inflammation in mice. Pharm Biol 54:2995–3000

    Article  CAS  PubMed  Google Scholar 

  • Hayashi H, Sudo H (2009) Economic importance of licorice. Plant Biotechnol 26:101–104

    Article  CAS  Google Scholar 

  • Hemmati F, Ghasemi R, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, Ahmadiani A (2014) Crosstalk between insulin and Toll-like receptor signaling pathways in the central nervous system. Mol Neurobiol 50:797–810

    Article  CAS  PubMed  Google Scholar 

  • Hibasami H, Iwase H, Yoshioka K, Takahashi H (2006) Glycyrrhetic acid (a metabolic substance and aglycon of glycyrrhizin) induces apoptosis in human hepatoma, promyelotic leukemia and stomach cancer cells. Int J Mol Med 17:215–219

    CAS  PubMed  Google Scholar 

  • Hoever G, Baltina L, Michaelis M, Kondratenko R, Baltina L, Tolstikov GA, Doerr HW, Cinatl J Jr (2005) Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J Med Chem 48:1256–1259

    Article  CAS  PubMed  Google Scholar 

  • Hou S, Zheng F, Li Y, Gao L, Zhang J (2014) The protective effect of glycyrrhizic acid on renal tubular epithelial cell injury induced by high glucose. Int J Mol Sci 15:15026–15043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kizhner T, Werman MJ (2002) Long-term fructose intake: biochemical consequences and altered renal histology in the male rat. Metabolism 51:1538–1547

    Article  CAS  PubMed  Google Scholar 

  • Kutlubay R, Oguz EO, Guven C, Can B, Sinik Z, Tuncay OL (2007) Histological and ultrastructural evidence for protective effects on aluminium-induced kidney damage by intraperitoneal administration of alpha-tocopherol. Int J Toxicol 26:95–101

    Article  CAS  PubMed  Google Scholar 

  • Lin JC (2003) Mechanism of action of glycyrrhizic acid in inhibition of Epstein-Barr virus replication in vitro. Antivir Res 59:41–47

    Article  CAS  PubMed  Google Scholar 

  • Lin JL, Yang YJ, Yang SS, Leu ML (1997) Aluminum utensils contribute to aluminum accumulation in patients with renal disease. Am J Kidney Dis 30:653–658

    Article  CAS  PubMed  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  • Mahieu ST, Gionotti M, Millen N, Elias MM (2003) Effect of chronic accumulation of aluminum on renal function, cortical renal oxidative stress and cortical renal organic anion transport in rats. Arch Toxicol 77:605–612

    Article  CAS  PubMed  Google Scholar 

  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  CAS  PubMed  Google Scholar 

  • Mudge DW, Johnson DW, Hawley CM, Campbell SB, Isbel NM, van Eps CL, Petrie JJ (2011) Do aluminium-based phosphate binders continue to have a role in contemporary nephrology practice? BMC Nephrol 12:20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakayama T, Kosugi T, Gersch M, Connor T, Sanchez-Lozada LG, Lanaspa MA, Roncal C, Perez-Pozo SE, Johnson RJ, Nakagawa T (2010) Dietary fructose causes tubulointerstitial injury in the normal rat kidney. Am J Physiol Ren Physiol 298:F712–F720

    Article  CAS  Google Scholar 

  • Oudot C, Lajoix AD, Jover B, Rugale C (2013) Dietary sodium restriction prevents kidney damage in high fructose-fed rats. Kidney Int 83:674–683

    Article  CAS  PubMed  Google Scholar 

  • Qiao Y, Xu L, Tao X, Yin L, Qi Y, Xu Y, Han X, Tang Z, Ma X, Liu K, Peng J (2018) Protective effects of dioscin against fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress, fibrosis, lipid metabolism and inflammation. Toxicol Lett 284:37–45

    Article  CAS  PubMed  Google Scholar 

  • Sargazi M, Shenkin A, Roberts NB (2006) Aluminium-induced injury to kidney proximal tubular cells: effects on markers of oxidative damage. J Trace Elem Med Biol 19:267–273

    Article  CAS  PubMed  Google Scholar 

  • Sen S, Roy M, Chakraborti AS (2011) Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats. J Pharm Pharmacol 63:287–296

    Article  CAS  PubMed  Google Scholar 

  • Sil R, Ray D, Chakraborti AS (2013) Glycyrrhizin ameliorates insulin resistance, hyperglycemia, dyslipidemia and oxidative stress in fructose-induced metabolic syndrome-X in rat model. Indian J Exp Biol 51:129–138

    CAS  PubMed  Google Scholar 

  • Smith KD (2009) Toll-like receptors in kidney disease. Curr Opin Nephrol Hypertens 18:189–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takii H, Kometani T, Nishimura T, Nakae T, Okada S, Fushiki T (2001) Antidiabetic effect of glycyrrhizin in genetically diabetic KK-ay mice. Biol Pharm Bull 24:484–487

    Article  CAS  PubMed  Google Scholar 

  • Wu CH, Chen AZ, Yen GC (2015) Protective effects of glycyrrhizic acid and 18beta-glycyrrhetinic acid against cisplatin-induced nephrotoxicity in BALB/c mice. J Agric Food Chem 63:1200–1209

    Article  CAS  PubMed  Google Scholar 

  • Zakaria S, Hasan RA, Mahmoud MF, El Fayoumi HM, Mahmoud AAA (2020) The concurrent exposure to aluminium and fructose induces liver injury in rats: protection by monoammonium glycyrrhizinate. Clin Exp Pharmacol Physiol 47:809–820

    Article  CAS  PubMed  Google Scholar 

  • Zheng QZ, Lou YJ (2003) Pathologic characteristics of immunologic injury in primary cultured rat hepatocytes and protective effect of glycyrrhizin in vitro. Acta Pharmacol Sin 24:771–777

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Dr. Rehab Hasan, Department of Histology, Faculty of Medicine, Al-Azhar University, Egypt, for her great effort in the histopathological examination.

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Author notes

  1. Amr A. A. Mahmoud

    Present address: Department of Pharmacology, Pharmacy Program, Oman College of Health Sciences, 114, Muscat, Oman

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt

    Noha A. Emara, Mona F. Mahmoud, Hassan M. El Fayoumi & Amr A. A. Mahmoud

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  1. Noha A. Emara
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  2. Mona F. Mahmoud
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  3. Hassan M. El Fayoumi
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Contributions

MFM, HME, and AAAM conceived and designed research. NAE conducted the experiments. NAE and AAAM analyzed the data. NAE and AAAM wrote the first draft of manuscript. MFM, HME, and AAAM revised and edited the manuscript. All the authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Amr A. A. Mahmoud.

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The study protocol and animal handling procedures were approved by the Ethical Committee for Animal Handling at Zagazig University (ECAH ZU), Faculty of Pharmacy, Zagazig University, Egypt based on the recommendations of the Weatherall report.

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The authors declare that there is no conflict of interest.

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Emara, N.A., Mahmoud, M.F., El Fayoumi, H.M. et al. The renoprotective effect of glycyrrhizic acid in insulin-resistant rats exposed to aluminum involves the inhibition of TLR4/NF-κB signaling pathway. Naunyn-Schmiedeberg's Arch Pharmacol 394, 863–872 (2021). https://doi.org/10.1007/s00210-020-02012-y

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