Journal of Ginseng Research

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

DOI QR Code

Reciprocal regulation of SIRT1 and AMPK by Ginsenoside compound K impedes the conversion from plasma cells to mitigate for podocyte injury in MRL/lpr mice in a B cell-specific manner

  • Ziyu Song (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Meng Jin (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Shenglong Wang (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Yanzuo Wu (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Qi Huang (Department of Endocrinology, The First Affiliated Hospital of Zhejiang Chinese Medical University) ;
  • Wangda Xu (First School of Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Yongsheng Fan (College of Basic Medical Science, Institute of Basic Research in Clinical Medicine, Zhejiang Chinese Medical University) ;
  • Fengyuan Tian (First School of Clinical Medicine, Zhejiang Chinese Medical University)
  • Received : 2023.06.28
  • Accepted : 2023.11.28
  • Published : 2024.03.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Deposition of immune complexes drives podocyte injury acting in the initial phase of lupus nephritis (LN), a process mediated by B cell involvement. Accordingly, targeting B cell subsets represents a potential therapeutic approach for LN. Ginsenoside compound K (CK), a bioavailable component of ginseng, possesses nephritis benefits in lupus-prone mice; however, the underlying mechanisms involving B cell subpopulations remain elusive. Methods: Female MRL/lpr mice were administered CK (40 mg/kg) intragastrically for 10 weeks, followed by measurements of anti-dsDNA antibodies, inflammatory chemokines, and metabolite profiles on renal samples. Podocyte function and ultrastructure were detected. Publicly available single-cell RNA sequencing data and flow cytometry analysis were employed to investigate B cell subpopulations. Metabolomics analysis was adopted. SIRT1 and AMPK expression were analyzed by immunoblotting and immunofluorescence assays. Results: CK reduced proteinuria and protected podocyte ultrastructure in MRL/lpr mice by suppressing circulating anti-dsDNA antibodies and mitigating systemic inflammation. It activated B cell-specific SIRT1 and AMPK with Rhamnose accumulation, hindering the conversion of renal B cells into plasma cells. This cascade facilitated the resolution of local renal inflammation. CK facilitated the clearance of deposited immune complexes, thus reinstating podocyte morphology and mobility by normalizing the expression of nephrin and SYNPO. Conclusions: Our study reveals the synergistic interplay between SIRT1 and AMPK, orchestrating the restoration of renal B cell subsets. This process effectively mitigates immune complex deposition and preserves podocyte function. Accordingly, CK emerges as a promising therapeutic agent, potentially alleviating the hyperactivity of renal B cell subsets during LN.

Keywords

Acknowledgement

The authors thank Betty Diamond for sharing the duplicate extraction in the single-cell genomics data. This work was supported by the Project of Zhejiang Provincial Administration of Traditional Chinese Medicine (2020ZZ009, 2021ZX005), the Advantage Discipline Construction Project from Zhejiang Provincial Hospital of Traditional Chinese Medicine (2D02311), the Tangjun Famous Traditional Chinese Medicine Doctor Inherit Workstation Project of Zhejiang Province of China (GZS2021021), and the Huangqi Famous Traditional Chinese Medicine Doctor Inherit Workstation Project of Zhejiang Province of China (GZS2020021).

References

  1. Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 2006;24:467-96. https://doi.org/10.1146/annurev.immunol.24.021605.090517
  2. Arazi A, et al. The immune cell landscape in kidneys of patients with lupus nephritis. Nat Immunol 2019;20:902-14. https://doi.org/10.1038/s41590-019-0398-x
  3. Furie RA, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2022;81:100-7. https://doi.org/10.1136/annrheumdis-2021-220920
  4. Gregersen JW, Jayne DR. B-cell depletion in the treatment of lupus nephritis. Nat Rev Nephrol 2012;8:505-14.
  5. Murphy G, Isenberg DA. New therapies for systemic lupus erythematosus - past imperfect, future tense. Nat Rev Rheumatol 2019;15:403-12. https://doi.org/10.1038/s41584-019-0235-5
  6. Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A. Survival of long-lived plasma cells is independent of antigen. Int Immunol 1998;10:1703-11. https://doi.org/10.1093/intimm/10.11.1703
  7. Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity 1998;8:363-72. https://doi.org/10.1016/S1074-7613(00)80541-5
  8. Radbruch A, et al. Competence and competition: the challenge of becoming a longlived plasma cell. Nat Rev Immunol 2006;6:741-50. https://doi.org/10.1038/nri1886
  9. Haley KE, et al. Podocyte injury elicits loss and recovery of cellular forces. Sci Adv 2018;4:eaap8030.
  10. Wright RD, Beresford MW. Podocytes contribute, and respond, to the inflammatory environment in lupus nephritis. Am J Physiol Ren Physiol 2018;315:F1683-94. https://doi.org/10.1152/ajprenal.00512.2017
  11. Rodgers JT, et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 2005;434:113-8. https://doi.org/10.1038/nature03354
  12. Singh V, Ubaid S. Role of silent information regulator 1 (SIRT1) in regulating oxidative stress and inflammation. Inflammation 2020;43:1589-98. https://doi.org/10.1007/s10753-020-01242-9
  13. Su PP, et al. Down-regulation of Risa improves podocyte injury by enhancing autophagy in diabetic nephropathy. Mil Med Res 2022;9:23.
  14. Fu Y, et al. Elevation of JAML promotes diabetic kidney disease by modulating podocyte lipid metabolism. Cell Metabol 2020;32:1052-1062 e8.
  15. Gan H, et al. B cell Sirt1 deacetylates histone and non-histone proteins for epigenetic modulation of AID expression and the antibody response. Sci Adv 2020;6:eaay2793.
  16. Cui J, Bai X, Chen X. Autophagy and diabetic nephropathy. Adv Exp Med Biol 2020;1207:487-94. https://doi.org/10.1007/978-981-15-4272-5_36
  17. Jang SG, et al. Metformin enhances the immunomodulatory potential of adiposederived mesenchymal stem cells through STAT1 in an animal model of lupus. Rheumatology (Oxford) 2020;59:1426-38. https://doi.org/10.1093/rheumatology/kez631
  18. Kim DH. Gut microbiota-mediated pharmacokinetics of ginseng saponins. J Ginseng Res 2018;42:255-63. https://doi.org/10.1016/j.jgr.2017.04.011
  19. Tian F, et al. Ginsenoside compound K increases glucagon-like peptide-1 release and L-cell abundance in db/db mice through TGR5/YAP signaling. Int Immunopharm 2022;113:109405.
  20. Tian F, et al. Compound K attenuates hyperglycemia by enhancing glucagon-like peptide-1 secretion through activating TGR5 via the remodeling of gut microbiota and bile acid metabolism. J Ginseng Res 2022;46:780-9. https://doi.org/10.1016/j.jgr.2022.03.006
  21. Oh JM, Chun S. Ginsenoside CK inhibits the early stage of adipogenesis via the AMPK, MAPK, and AKT signaling pathways. Antioxidants (Basel) 2022;11.
  22. Kim MS, et al. Compound K modulates fatty acid-induced lipid droplet formation and expression of proteins involved in lipid metabolism in hepatocytes. Liver Int 2013;33:1583-93.
  23. Lin TJ, et al. Accelerated and severe lupus nephritis benefits from M1, an active metabolite of ginsenoside, by regulating NLRP3 inflammasome and T cell functions in mice. Front Immunol 2019;10:1951.
  24. Theofilopoulos AN, Dixon FJ. Murine models of systemic lupus erythematosus. Adv Immunol 1985;37:269-390.
  25. Song W, Wei L, Du Y, Wang Y, Jiang S. Protective effect of ginsenoside metabolite compound K against diabetic nephropathy by inhibiting NLRP3 inflammasome activation and NF-kappaB/p38 signaling pathway in high-fat diet/streptozotocininduced diabetic mice. Int Immunopharm 2018;63:227-38. https://doi.org/10.1016/j.intimp.2018.07.027
  26. Kosti P, et al. Hypoxia-sensing CAR T cells provide safety and efficacy in treating solid tumors. Cell Rep Med 2021;2:100227.
  27. Yang M, et al. AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1-Bcl-6 axis-mediated B-cell differentiation. Signal Transduct Targeted Ther 2021;6:341.
  28. Schwickert TA, et al. Ikaros prevents autoimmunity by controlling anergy and Tolllike receptor signaling in B cells. Nat Immunol 2019;20:1517-29. https://doi.org/10.1038/s41590-019-0490-2
  29. Kikawada E, Lenda DM, Kelley VR. IL-12 deficiency in MRL-Fas(lpr) mice delays nephritis and intrarenal IFN-gamma expression, and diminishes systemic pathology. J Immunol 2003;170:3915-25. https://doi.org/10.4049/jimmunol.170.7.3915
  30. Van Belle K, et al. Comparative in vitro immune stimulation analysis of primary human B cells and B cell lines. J Immunol Res 2016;2016:5281823.
  31. Weinberger M, Simoes FC, Patient R, Sauka-Spengler T, Riley PR. Functional heterogeneity within the developing zebrafish epicardium. Dev Cell 2020;52:574-590 e6.
  32. Liu J, et al. Investigating the mechanisms of jieduquyuziyin prescription improves lupus nephritis and fibrosis via FXR in MRL/lpr mice. Oxid Med Cell Longev 2022; 2022:4301033.
  33. Hou LF, et al. Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses. Arthritis Rheum 2011;63:2445-55. https://doi.org/10.1002/art.30392
  34. Li X, et al. Nephrin preserves podocyte viability and glomerular structure and function in adult kidneys. J Am Soc Nephrol 2015;26:2361-77. https://doi.org/10.1681/ASN.2014040405
  35. Yu H, et al. Synaptopodin limits TRPC6 podocyte surface expression and attenuates proteinuria. J Am Soc Nephrol 2016;27:3308-19. https://doi.org/10.1681/ASN.2015080896
  36. Yokogawa M, et al. Epicutaneous application of toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: a new model of systemic Lupus erythematosus. Arthritis Rheumatol 2014;66:694-706. https://doi.org/10.1002/art.38298
  37. Maeda K, et al. CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. J Clin Invest 2018;128:3445-59. https://doi.org/10.1172/JCI99507
  38. Bautista DA, Pegg RB, Shand PJ. Effect of L-glucose and D-tagatose on bacterial growth in media and a cooked cured ham product. J Food Protect 2000;63:71-7. https://doi.org/10.4315/0362-028X-63.1.71
  39. Choi M, et al. L-rhamnose induces browning in 3T3-L1 white adipocytes and activates HIB1B brown adipocytes. IUBMB Life 2018;70:563-73. https://doi.org/10.1002/iub.1750
  40. Chu Q, et al. Purified Tetrastigma hemsleyanum vines polysaccharide attenuates EC-induced toxicity in Caco-2 cells and Caenorhabditis elegans via DAF-16/FOXO pathway. Int J Biol Macromol 2020;150:1192-202. https://doi.org/10.1016/j.ijbiomac.2019.10.128
  41. Jiang P, et al. Structure and potential anti-fatigue mechanism of polysaccharides from Bupleurum chinense DC. Carbohydr Polym 2023;306:120608.
  42. Greka A, Mundel P. Balancing calcium signals through TRPC5 and TRPC6 in podocytes. J Am Soc Nephrol 2011;22:1969-80. https://doi.org/10.1681/ASN.2011040370
  43. Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol 2012;74:299-323.
  44. Brahler S, et al. Intravital and kidney slice imaging of podocyte membrane dynamics. J Am Soc Nephrol 2016;27:3285-90. https://doi.org/10.1681/ASN.2015121303
  45. Hackl MJ, et al. Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in new mouse models with fluorescent lineage tags. Nat Med 2013;19:1661-6.
  46. Qu C, et al. Three-dimensional visualization of the podocyte actin network using integrated membrane extraction, electron microscopy, and machine learning. J Am Soc Nephrol 2022;33:155-73.
  47. Tian F, et al. The ginsenoside metabolite compound K stimulates glucagon-like peptide-1 secretion in NCI-H716 cells by regulating the RhoA/ROCKs/YAP signaling pathway and cytoskeleton formation. J Pharmacol Sci 2021;145:88-96. https://doi.org/10.1016/j.jphs.2020.11.005
  48. Agrawal S, Guess AJ, Chanley MA, Smoyer WE. Albumin-induced podocyte injury and protection are associated with regulation of COX-2. Kidney Int 2014;86:1150-60. https://doi.org/10.1038/ki.2014.196
  49. Peterson KS, et al. Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. J Clin Invest 2004;113:1722-33.
  50. Davidson A. Editorial: autoimmunity to vimentin and lupus nephritis. Arthritis Rheumatol 2014;66:3251-4.
  51. Myles A, Gearhart PJ, Cancro MP. Signals that drive T-bet expression in B cells. Cell Immunol 2017;321:3-7.
  52. Sequeira J, et al. sirt1-null mice develop an autoimmune-like condition. Exp Cell Res 2008;314:3069-74. https://doi.org/10.1016/j.yexcr.2008.07.011
  53. Xu Z, Zan H, Pone EJ, Mai T, Casali P. Immunoglobulin class-switch DNA recombination: induction, targeting and beyond. Nat Rev Immunol 2012;12:517-31. https://doi.org/10.1038/nri3216
  54. Zan H, Casali P. Epigenetics of peripheral B-cell differentiation and the antibody response. Front Immunol 2015;6:631.
  55. Cheng D, et al. Inhibitory effect on HT-29 colon cancer cells of a water-soluble polysaccharide obtained from highland barley. Int J Biol Macromol 2016;92:88-95. https://doi.org/10.1016/j.ijbiomac.2016.06.099
  56. Liu N, Dong Z, Zhu X, Xu H, Zhao Z. Characterization and protective effect of Polygonatum sibiricum polysaccharide against cyclophosphamide-induced immunosuppression in Balb/c mice. Int J Biol Macromol 2018;107:796-802. https://doi.org/10.1016/j.ijbiomac.2017.09.051
  57. Novotna R, et al. Hesperidin, hesperetin, rutinose, and rhamnose act as skin antiaging agents. Molecules 2023;28.