Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenoside Rb3 ameliorates podocyte injury under hyperlipidemic conditions via PPARδ- or SIRT6-mediated suppression of inflammation and oxidative stress

  • Heeseung Oh (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Wonjun Cho (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Seung Yeon Park (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • A.M. Abd El-Aty (Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University) ;
  • Ji Hoon Jeong (Department of Pharmacology, College of Medicine, Chung-Ang University) ;
  • Tae Woo Jung (Department of Pharmacology, College of Medicine, Chung-Ang University)
  • Received : 2022.07.08
  • Accepted : 2022.11.23
  • Published : 2023.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Rb3 is a ginsenoside with anti-inflammatory properties in many cell types and has been reported to attenuate inflammation-related metabolic diseases such as insulin resistance, nonalcoholic fatty liver disease, and cardiovascular disease. However, the effect of Rb3 on podocyte apoptosis under hyperlipidemic conditions, which contributes to the development of obesity-mediated renal disease, remains unclear. In the current study, we aimed to investigate the effect of Rb3 on podocyte apoptosis in the presence of palmitate and explore its underlying molecular mechanisms. Methods: Human podocytes (CIHP-1 cells) were exposed to Rb3 in the presence of palmitate as a model of hyperlipidemia. Cell viability was assessed by MTT assay. The effects of Rb3 on the expression of various proteins were analyzed by Western blotting. Apoptosis levels were determined by MTT assay, caspase 3 activity assay, and cleaved caspase 3 expression. Results: We found that Rb3 treatment alleviated the impairment of cell viability and increased caspase 3 activity as well as inflammatory markers in palmitate-treated podocytes. Treatment with Rb3 dosedependently increased PPARδ and SIRT6 expression. Knockdown of PPARδ or SIRT6 reduced the effects of Rb3 on apoptosis as well as inflammation and oxidative stress in cultured podocytes. Conclusions: The current results suggest that Rb3 alleviates inflammation and oxidative stress via PPARδ-or SIRT6-mediated signaling, thereby attenuating apoptosis in podocytes in the presence of palmitate. The present study provides Rb3 as an effective strategy for treating obesity-mediated renal injury.

Keywords

Acknowledgement

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2021R1F1A1050004 and No. 2022R1A2B5B01001453).

References

  1. Kovesdy CP, Furth SL, Zoccali C, World Kidney Day Steering C. Obesity and kidney disease: hidden consequences of the epidemic. Can J Kidney Health Dis 2017;4:2054358117698669.
  2. Kosmas CE, Silverio D, Tsomidou C, Salcedo MD, Montan PD, Guzman E. The impact of insulin resistance and chronic kidney disease on inflammation and cardiovascular disease. Clin Med Insights Endocrinol Diabetes 2018;11:1179551418792257.
  3. Saurus P, Kuusela S, Lehtonen E, Hyvonen ME, Ristola M, Fogarty CL, Tienari J, Lassenius MI, Forsblom C, Lehto M, et al. Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway. Cell Death Dis 2015;6:e1752.
  4. Zhu YT, Wan C, Lin JH, Hammes HP, Zhang C. Mitochondrial oxidative stress and cell death in podocytopathies. Biomolecules 2022;12(3).
  5. Wang MZ, Wang J, Cao DW, Tu Y, Liu BH, Yuan CC, Li H, Fang QJ, Chen JX, Fu Y, et al. Fucoidan alleviates renal fibrosis in diabetic kidney disease via inhibition of NLRP3 inflammasome-mediated podocyte pyroptosis. Front Pharmacol 2022;13:790937.
  6. Fan W, Huang Y, Zheng H, Li S, Li Z, Yuan L, Cheng X, He C, Sun J. Ginsenosides for the treatment of metabolic syndrome and cardiovascular diseases: pharmacology and mechanisms. Biomed Pharmacother 2020;132:110915.
  7. Xu H, Liu M, Chen G, Wu Y, Xie L, Han X, Zhang G, Tan Z, Ding W, Fan H, et al. Anti-inflammatory effects of ginsenoside Rb3 in LPS-induced macrophages through direct inhibition of TLR4 signaling pathway. Front Pharmacol 2022;13:714554.
  8. Jiang Y, Sui D, Li M, Xu H, Yu X, Liu J, Yu Q. Ginsenoside Re improves inflammation and fibrosis in hepatic tissue by upregulating PPARgamma expression and inhibiting oxidative stress in db/db mice. Evid Based Complement Alternat Med 2021;2021:9003603.
  9. Ma CH, Chou WC, Wu CH, Jou IM, Tu YK, Hsieh PL, Tsai KL. Ginsenoside Rg3 attenuates TNF-alpha-induced damage in chondrocytes through regulating SIRT1-mediated anti-apoptotic and anti-inflammatory mechanisms. Antioxidants (Basel) 2021;10(12).
  10. Wang Y, Dong J, Liu P, Lau CW, Gao Z, Zhou D, Tang J, Ng CF, Huang Y. Ginsenoside Rb3 attenuates oxidative stress and preserves endothelial function in renal arteries from hypertensive rats. Br J Pharmacol 2014;171(13):3171-81. https://doi.org/10.1111/bph.12660
  11. Oh SJ, Oh Y, Ryu IW, Kim K, Lim CJ. Protective properties of ginsenoside Rb3 against UV-B radiation-induced oxidative stress in HaCaT keratinocytes. Biosci Biotechnol Biochem 2016;80(1):95-103. https://doi.org/10.1080/09168451.2015.1075862
  12. Li Q, Zeng Y, Jiang Q, Wu C, Zhou J. Role of mTOR signaling in the regulation of high glucose-induced podocyte injury. Exp Ther Med 2019;17(4):2495-502. https://doi.org/10.3892/etm.2019.7236
  13. Wang T, Gao Y, Wang X, Shi Y, Xu J, Wu B, He J, Li Y. Calpain-10 drives podocyte apoptosis and renal injury in diabetic nephropathy. Diabetes Metab Syndr Obes 2019;12:1811-20. https://doi.org/10.2147/DMSO.S217924
  14. Hall JE, Mouton AJ, da Silva AA, Omoto ACM, Wang Z, Li X, do Carmo JM. Obesity, kidney dysfunction, and inflammation: interactions in hypertension. Cardiovasc Res 2021;117(8):1859-76. https://doi.org/10.1093/cvr/cvaa336
  15. Sun Y, Ge X, Li X, He J, Wei X, Du J, Sun J, Li X, Xun Z, Liu W, et al. High-fat diet promotes renal injury by inducing oxidative stress and mitochondrial dysfunction. Cell Death Dis 2020;11(10):914.
  16. Jung TW, Lee SH, Kim HC, Bang JS, Abd El-Aty AM, Hacimuftuoglu A, Shin YK, Jeong JH. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARdelta-dependent pathways in skeletal muscle of mice. Exp Mol Med 2018;50(9):1-11. https://doi.org/10.1038/s12276-018-0147-5
  17. Wan J, Jiang L, Lu Q, Ke L, Li X, Tong N. Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells. Biochem Biophys Res Commun 2010;391(3):1567-72. https://doi.org/10.1016/j.bbrc.2009.12.127
  18. Xiong X, Sun X, Wang Q, Qian X, Zhang Y, Pan X, Dong XC. SIRT6 protects against palmitate-induced pancreatic beta-cell dysfunction and apoptosis. J Endocrinol 2016;231(2):159-65. https://doi.org/10.1530/JOE-16-0317
  19. Schell C, Huber TB. The evolving complexity of the podocyte cytoskeleton. J Am Soc Nephrol 2017;28(11):3166-74. https://doi.org/10.1681/ASN.2017020143
  20. Martinez-Garcia C, Izquierdo-Lahuerta A, Vivas Y, Velasco I, Yeo TK, Chen S, Medina-Gomez G. Renal lipotoxicity-associated inflammation and insulin resistance affects actin cytoskeleton organization in podocytes. PLoS One 2015;10(11):e0142291.
  21. Wickman C, Kramer H. Obesity and kidney disease: potential mechanisms. Semin Nephrol 2013;33(1):14-22. https://doi.org/10.1016/j.semnephrol.2012.12.006
  22. Xu S, Nam SM, Kim JH, Das R, Choi SK, Nguyen TT, Quan X, Choi SJ, Chung CH, Lee EY, et al. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis 2015;6:e1976.
  23. Jucker BM, Yang D, Casey WM, Olzinski AR, Williams C, Lenhard SC, Legos JJ, Hawk CT, Sarkar SK, Newsholme SJ. Selective PPARdelta agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study. Am J Physiol Endocrinol Metab 2007;293(5):E1256-64. https://doi.org/10.1152/ajpendo.00218.2007
  24. Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O'Rahilly S, et al. International union of pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 2006;58(4):726-41.
  25. Vargas-Sanchez K, Vargas L, Urrutia Y, Beltran I, Rossi AB, Lozano HY, Guarin J, Losada-Barragan M. PPARalpha and PPARbeta/delta are negatively correlated with proinflammatory markers in leukocytes of an obese pediatric population. J Inflamm (Lond) 2020;17(1):35.
  26. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 2008;7(6):496-507. https://doi.org/10.1016/j.cmet.2008.04.003
  27. Pesant M, Sueur S, Dutartre P, Tallandier M, Grimaldi PA, Rochette L, Connat JL. Peroxisome proliferator-activated receptor delta (PPARdelta) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis. Cardiovasc Res 2006;69(2):440-9. https://doi.org/10.1016/j.cardiores.2005.10.019
  28. Riserus U, Sprecher D, Johnson T, Olson E, Hirschberg S, Liu A, Fang Z, Hegde P, Richards D, Sarov-Blat L, et al. Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 2008;57(2):332-9. https://doi.org/10.2337/db07-1318
  29. Kuang J, Chen L, Tang Q, Zhang J, Li Y, He J. The role of Sirt6 in obesity and diabetes. Front Physiol 2018;9:135.
  30. He Y, Yang G, Sun L, Gao H, Yao F, Jin Z, Zheng Z, Chen L, Wang W, Zheng N, et al. SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular endothelial cells. Int Immunopharmacol 2021;99:107926.
  31. Jung TW, Park J, Sun JL, Ahn SH, Abd El-Aty AM, Hacimuftuoglu A, Kim HC, Shim JH, Shin S, Jeong JH. Administration of kynurenic acid reduces hyperlipidemia-induced inflammation and insulin resistance in skeletal muscle and adipocytes. Mol Cell Endocrinol 2020;518:110928.
  32. Wang Y, Zhang S, Ma Y, Xiang A, Sun H, Song J, Yang W, Li X, Xu H. Melatonin protected against myocardial infarction injury in rats through a Sirt6-dependent antioxidant pathway. Adv Clin Exp Med 2022;31(3):277-84. https://doi.org/10.17219/acem/112060
  33. Greiten LE, Zhang B, Roos CM, Hagler M, Jahns FP, Miller JD. Sirtuin 6 protects against oxidative stress and vascular dysfunction in mice. Front Physiol 2021;12:753501.