Nutrition Research and Practice

  • 제18권2호
  • /
  • Pages.210-222
  • /
  • 2024
  • /
  • 1976-1457(pISSN)
  • /
  • 2005-6168(eISSN)
한국영양학회 (The Korean Nutrition Society)
권호 표지
DOI QR코드

DOI QR Code

Melittin induces autophagy to alleviate chronic renal failure in 5/6-nephrectomized rats and angiotensin II-induced damage in podocytes

  • Yufan Zhang (TCM Department, Shanghai Yangpu District Kongjiang Hospital) ;
  • Huaping Xu (Department of Physical Education, Shanghai University of Traditional Chinese Medicine) ;
  • Hongwei Qiao (Geriatric Department, Shanghai Yangpu District Kongjiang Hospital) ;
  • Ya Zhao (Cardiology Department, Shanghai Yangpu District Kongjiang Hospital) ;
  • Minmin Jiang (Geriatric Department, Shanghai Yangpu District Kongjiang Hospital)
  • 투고 : 2024.01.17
  • 심사 : 2024.03.18
  • 발행 : 2024.04.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

BACKGROUND/OBJECTIVES: Chronic renal failure (CRF) is a complex pathological condition that lacks a cure. Certain Chinese medicines, such as melittin, a major component in bee venom, have shown efficacy in treating CRF patients. On the other hand, the mechanisms underlying the therapeutic effects of melittin are unclear. MATERIALS/METHODS: A 5/6 nephrectomy model (5/6 Nx) of renal failure was established on rats for in vivo assays, and mouse podocyte clone 5 (MPC5) mouse podocyte cells were treated with angiotensin II (AngII) to establish an in vitro podocyte damage model. The 24-h urine protein, serum creatinine, and blood urea nitrogen levels were evaluated after one, 2, and 4 weeks. Hematoxylin and eosin staining, Masson staining, and periodic acid-Schiff staining were used to examine the pathological changes in kidney tissues. A cell counting kit 8 assay was used to assess the cell viability. Reverse transcription polymerase chain reaction and Western blot were used to assess the mRNA and protein levels in the cells, respectively. RESULTS: In the rat 5/6 Nx, melittin reduced the 24-h urinary protein excretion and the serum creatinine and blood urea nitrogen levels. Furthermore, the renal pathology was improved in the melittin-treated 5/6 Nx rats. Melittin promoted podocin, nephrin, Beclin 1, and the LC3II/LC3I ratio and inhibited phosphorylated mammalian target of rapamycin (mTOR)/mTOR in 5/6 Nx-induced rats and AngII-induced MPC5 mouse podocyte cells. Moreover, inhibiting autophagy with 3-MA weakened the effects of melittin on podocin, nephrin, and the LC3II/LC3I ratio in podocytes. CONCLUSION: Melittin may offer protection against kidney injury, probably by regulating podocyte autophagy. These results provide the theoretical basis for applying melittin in CRF therapy.

키워드

과제정보

This study is supported by the Topic of Shanghai Health Commission (202040026).

참고문헌

  1. Chen TK, Knicely DH, Grams ME. Chronic kidney disease diagnosis and management: a review. JAMA 2019;322:1294-304.
  2. Bryer JS, Susztak K. Screening drugs for kidney disease: targeting the podocyte. Cell Chem Biol 2018;25:126-7.
  3. Akyuz Ozdemir A, Erdal R, Haberal M. Factors predisposing to the use of complementary therapies in patients with chronic renal failure. Exp Clin Transplant 2018;16 Suppl 1:64-9.
  4. Tagawa A, Yasuda M, Kume S, Yamahara K, Nakazawa J, Chin-Kanasaki M, Araki H, Araki S, Koya D, Asanuma K, et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 2016;65:755-67.
  5. Guo H, Bechtel-Walz W. The interplay of autophagy and oxidative stress in the kidney: what do we know? Nephron 2023;147:627-42.
  6. Xue L, Pan Z, Yin Q, Zhang P, Zhang J, Qi W. Liraglutide promotes autophagy by regulating the AMPK/mTOR pathway in a rat remnant kidney model of chronic renal failure. Int Urol Nephrol 2019;51:2305-13.
  7. Li YY, Tian ZH, Pan GH, Zhao P, Pan DJ, Zhang JQ, Ye LY, Zhang FR, Xu XD. Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy. Front Pharmacol 2022;13:977284.
  8. Wang Y, Feng Y, Li M, Yang M, Shi G, Xuan Z, Yin D, Xu F. Traditional Chinese medicine in the treatment of chronic kidney diseases: theories, applications, and mechanisms. Front Pharmacol 2022;13:917975.
  9. Yoshino T, Horiba Y, Mimura M, Watanabe K. Oral Astragalus root supplementation for mild to moderate chronic kidney disease: a self-controlled case-series. Front Pharmacol 2022;13:775798.
  10. Sun X, Li P, Lin H, Ni Z, Zhan Y, Cai G, Liu C, Chen Q, Wang W, Wang X, et al. Efficacy and safety of Abelmoschus manihot in treating chronic kidney diseases: a multicentre, open-label and single-arm clinical trial. Phytomedicine 2022;99:154011.
  11. Li J, Ke T, He C, Cao W, Wei M, Zhang L, Zhang JX, Wang W, Ma J, Wang ZR, et al. The anti-arthritic effects of synthetic melittin on the complete Freund's adjuvant-induced rheumatoid arthritis model in rats. Am J Chin Med 2010;38:1039-49.
  12. An HJ, Kim JY, Kim WH, Han SM, Park KK. The protective effect of melittin on renal fibrosis in an animal model of unilateral ureteral obstruction. Molecules 2016;21:1137.
  13. Kim JY, Leem J, Hong HL. Melittin ameliorates endotoxin-induced acute kidney injury by inhibiting inflammation, oxidative stress, and cell death in mice. Oxid Med Cell Longev 2021;2021:8843051.
  14. He SD, Tan N, Sun CX, Liao KH, Zhu HJ, Luo XG, Zhang JY, Li DY, Huang SG. Treatment with melittin induces apoptosis and autophagy of Fibroblast-Like Synoviocytes in patients with rheumatoid arthritis. Curr Pharm Biotechnol 2020;21:734-40.
  15. Memariani H, Memariani M. Melittin as a promising anti-protozoan peptide: current knowledge and future prospects. AMB Express 2021;11:69.
  16. Aghighi Z, Ghorbani Z, Moghaddam MH, Fathi M, Abdollahifar MA, Soleimani M, Karimzadeh F, Rasoolijazi H, Aliaghaei A. Melittin ameliorates motor function and prevents autophagy-induced cell death and astrogliosis in rat models of cerebellar ataxia induced by 3-acetylpyridine. Neuropeptides 2022;96:102295.
  17. Sun Q, Chen W, Wang M, Zheng P, Gao M, Song F, Li C. A "Chase and Block" strategy for enhanced cancer therapy with hypoxia-promoted photodynamic therapy and autophagy inhibition based on upconversion nanocomposites. Adv Healthc Mater 2023;12:e2301087.
  18. Yang RC, Zhu XL, Wang J, Wan F, Zhang HQ, Lin Y, Tang XL, Zhu B. Bone marrow mesenchymal stem cells attenuate the progression of focal segmental glomerulosclerosis in rat models. BMC Nephrol 2018;19:335.
  19. Ware K, Brodsky P, Satoskar AA, Nadasdy T, Nadasdy G, Wu H, Rovin BH, Bhatt U, Von Visger J, Hebert LA, et al. Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation. J Am Soc Nephrol 2011;22:1856-62.
  20. Yang L, He X, Zhi D, Xue Y, Gong X, Dong K, Tian Y. Melittin promotes dexamethasone in the treatment of adjuvant rheumatoid arthritis in rats. Front Pharmacol 2024;15:1338432.
  21. Naji KM, Al-Khatib BY, Al-Haj NS, D'souza MR. Hepatoprotective activity of melittin on isoniazid- and rifampicin-induced liver injuries in male albino rats. BMC Pharmacol Toxicol 2021;22:39.
  22. Duan X, Chen C, Liu X, Wang T, Feng S, Li J, Li G. Interference of periostin attenuates pathological changes, proinflammatory markers and renal fibrosis in diabetic kidney injury. Genes Genomics 2023;45:1389-97.
  23. Ji J, He L. Effect of Kangxianling decoction on expression of TGF-β1/Smads and extracellular matrix deposition. Evid Based Complement Alternat Med 2019;2019:5813549.
  24. Zhang Z, Zhang Y, Ning G, Deb DK, Kong J, Li YC. Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proc Natl Acad Sci U S A 2008;105:15896-901.
  25. Moon DO, Park SY, Lee KJ, Heo MS, Kim KC, Kim MO, Lee JD, Choi YH, Kim GY. Bee venom and melittin reduce proinflammatory mediators in lipopolysaccharide-stimulated BV2 microglia. Int Immunopharmacol 2007;7:1092-101.
  26. Du YR, Xiao Y, Lu ZM, Ding J, Xie F, Fu H, Wang Y, Strong JA, Zhang JM, Chen J. Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways. Biochem Biophys Res Commun 2011;408:32-7.
  27. Ding J, Xiao Y, Lu D, Du YR, Cui XY, Chen J. Effects of SKF-96365, a TRPC inhibitor, on melittin-induced inward current and intracellular Ca2+ rise in primary sensory cells. Neurosci Bull 2011;27:135-42.
  28. Fukuyo Y, Nakamura T, Bubenshchikova E, Powell R, Tsuji T, Janknecht R, Obara T. Nephrin and Podocin functions are highly conserved between the zebrafish pronephros and mammalian metanephros. Mol Med Rep 2014;9:457-65.
  29. Menon MB, Dhamija S. Beclin 1 phosphorylation - at the center of autophagy regulation. Front Cell Dev Biol 2018;6:137.
  30. Tanida I, Ueno T, Kominami E. LC3 and autophagy. Methods Mol Biol 2008;445:77-88.
  31. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015;125:25-32.
  32. Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov 2016;15:568-88.
  33. Lee HW, Khan SQ, Faridi MH, Wei C, Tardi NJ, Altintas MM, Elshabrawy HA, Mangos S, Quick KL, Sever S, et al. A podocyte-based automated screening assay identifies protective small molecules. J Am Soc Nephrol 2015;26:2741-52.
  34. Lin Q, Banu K, Ni Z, Leventhal JS, Menon MC. Podocyte autophagy in homeostasis and disease. J Clin Med 2021;10:1184.
  35. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15:1101-11.
  36. Leventhal JS, Wyatt CM, Ross MJ. Recycling to discover something new: the role of autophagy in kidney disease. Kidney Int 2017;91:4-6.
  37. Li H, Peng X, Wang Y, Cao S, Xiong L, Fan J, Wang Y, Zhuang S, Yu X, Mao H. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy 2016;12:1472-86.
  38. Andrade L, Rodrigues CE, Gomes SA, Noronha IL. Acute kidney injury as a condition of renal senescence. Cell Transplant 2018;27:739-53.
  39. Choi M, Ryu J, Vu HD, Kim D, Youn YJ, Park MH, Huynh PT, Hwang GB, Youn SW, Jeong YH. Transferrin-conjugated melittin-loaded l-arginine-coated iron oxide nanoparticles for mitigating beta-amyloid pathology of the 5XFAD mouse brain. Int J Mol Sci 2023;24:14954.
  40. Karimi G, Fatemi S, Memar B, Khorrami MB, Amali A, Sadeghi M, Esmaeili SA, Riahi-Zanjani B. Melittin as a safe compound to BALB/c mice immune system; a tiered approach immunotoxicity screening. BMC Complement Med Ther 2023;23:377.
  41. Lv C, Zhang Z, Zhao T, Han MF, Jia DP, Su LZ, Huang F, Wang FZ, Fang FF, Li B. The anti-tumour effect of Mel and its role in autophagy in human hepatocellular carcinoma cells. Am J Transl Res 2019;11:931-41.
  42. Yu JE, Kim Y, Hong DE, Lee DW, Chang JY, Yoo SS, Kim MJ, Son DJ, Yun J, Han SB, et al. Bee venom triggers autophagy-induced apoptosis in human lung cancer cells via the mTOR signaling pathway. J Oncol 2022;2022:8916464.
  43. Lv C, Chen J, Huang F, Fang F, Li B. Melittin inhibits the proliferation migration and invasion of HCC cells by regulating ADAMTS9-AS2 demethylation. Toxicon 2023;222:106996.
  44. Lim HN, Baek SB, Jung HJ. Bee venom and its peptide component melittin suppress growth and migration of melanoma cells via inhibition of PI3K/AKT/mTOR and MAPK pathways. Molecules 2019;24:929.
  45. Jeong YJ, Choi Y, Shin JM, Cho HJ, Kang JH, Park KK, Choe JY, Bae YS, Han SM, Kim CH, et al. Melittin suppresses EGF-induced cell motility and invasion by inhibiting PI3K/Akt/mTOR signaling pathway in breast cancer cells. Food Chem Toxicol 2014;68:218-25.
  46. Fan XG, Pei SY, Zhou D, Zhou PC, Huang Y, Hu XW, Li T, Wang Y, Huang ZB, Li N. Melittin ameliorates inflammation in mouse acute liver failure via inhibition of PKM2-mediated Warburg effect. Acta Pharmacol Sin 2021;42:1256-66.
  47. Gu H, An HJ, Gwon MG, Bae S, Leem J, Lee SJ, Han SM, Zouboulis CC, Park KK. Bee venom and its major component melittin attenuated Cutibacterium acnes- and IGF-1-induced acne vulgaris via inactivation of Akt/mTOR/SREBP signaling pathway. Int J Mol Sci 2022;23:3152.
  48. Moreira Castro BF, Nunes da Silva C, Barbosa Cordeiro LP, Pereira de Freitas Cenachi S, Vasconcelos-Santos DV, Machado RR, Dias Heneine LG, Silva LM, Silva-Cunha A, Fialho SL. Low-dose melittin is safe for intravitreal administration and ameliorates inflammation in an experimental model of uveitis. Curr Res Pharmacol Drug Discov 2022;3:100107.