Online first
Original paper
Published online: 2024-07-22

open access

Page views 62
Article views/downloads 30
Get Citation

Connect on Social Media

Connect on Social Media

Dioscin attenuates lupus nephritis in NZB/W F1 mice by decreasing NF-κB activation and NLRP3 inflammasome

Yaling Xu1, Han Li2

Abstract

Introduction. Dioscin, a natural steroid saponin, has anticancer, anti-inflammatory, anti-hyperlipidemic, and glycemic capabilities. This study focused on dioscin roles and its related mechanisms in experimental lupus nephritis.

Materials and methods. Lupus-prone NZB/W F1 mice were intragastrically administered with dioscin, prednisone or vehicle, and kidney, urine and blood samples were harvested after the mice were sacrificed. Proteinuria, blood urea nitrogen (BUN), creatinine, anti-dsDNA, IL-1β, and IL-18 levels in serum as well as IFN-γ, IL-6, IL-17 and TNF-α levels in kidney tissues were assessed. Renal histopathology was examined through hematoxylin-eosin staining. IgG and C3 expression in kidney was evaluated using immunofluorescence staining. The number of glomerular F4/80-positive cells and NLRP3-positive cells was determined by immunohistochemical staining. The protein expression was examined by western blotting.

Results. Dioscin alleviated lupus nephritis in NZB/W F1 mice. Dioscin declined serum anti-dsDNA level, prevented deposition of immune complexes in renal glomeruli, and inhibited the inflammatory response and infiltration of macrophages into mouse kidneys. Dioscin inhibited NF-κB and NLRP3 inflammasome in NZB/W F1 mice.

Conclusions. Dioscin ameliorates lupus nephritis through inhibition of NLRP3 inflammasome and NF-κB signaling.

Article available in PDF format

View PDF Download PDF file

References

  1. Tian J, Zhang D, Yao Xu, et al. Global epidemiology of systemic lupus erythematosus: a comprehensive systematic analysis and modelling study. Ann Rheum Dis. 2023; 82(3): 351–356.
  2. Hanly JG, O'Keeffe AG, Su Li, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford). 2016; 55(2): 252–262.
  3. Li D, Shi G, Wang J, et al. Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells. Arthritis Res Ther. 2019; 21(1): 105.
  4. Kudose S, Santoriello D, Bomback A, et al. Sensitivity and specificity of pathologic findings to diagnose lupus nephritis. Clin J Am Soc Nephrol. 2019; 14(11): 1605–1615.
  5. Chalmers SA, Chitu V, Ramanujam M, et al. Therapeutic targeting of macrophages in lupus nephritis. Discov Med. 2015; 20(108): 43–49.
  6. Yung S, Cheung KF, Zhang Q, et al. Anti-dsDNA antibodies bind to mesangial annexin II in lupus nephritis. J Am Soc Nephrol. 2010; 21(11): 1912–1927.
  7. Anders HJ, Saxena R, Zhao MH, et al. Lupus nephritis. Nat Rev Dis Primers. 2020; 6(1): 7.
  8. Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol. 2023; 41: 301–316.
  9. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013; 13(6): 397–411.
  10. Huang T, Yin H, Ning W, et al. Expression of inflammasomes NLRP1, NLRP3 and AIM2 in different pathologic classification of lupus nephritis. Clin Exp Rheumatol. 2020; 38(4): 680–690.
  11. Honarpisheh M, Desai J, Marschner JA, et al. Regulated necrosis-related molecule mRNA expression in humans and mice and in murine acute tissue injury and systemic autoimmunity leading to progressive organ damage, and progressive fibrosis. Biosci Rep. 2016; 36(6).
  12. Bonomini F, Dos Santos M, Veronese FV, et al. NLRP3 Inflammasome Modulation by Melatonin Supplementation in Chronic Pristane-Induced Lupus Nephritis. Int J Mol Sci. 2019; 20(14).
  13. Fu R, Guo C, Wang S, et al. Podocyte activation of NLRP3 inflammasomes contributes to the development of proteinuria in lupus nephritis. Arthritis Rheumatol. 2017; 69(8): 1636–1646.
  14. Fu R, Xia Y, Li M, et al. Pim-1 as a therapeutic target in lupus nephritis. Arthritis Rheumatol. 2019; 71(8): 1308–1318.
  15. Wu CY, Hua KF, Chu CL, et al. Tris DBA ameliorates accelerated and severe lupus nephritis in mice by activating regulatory t cells and autophagy and inhibiting the NLRP3 inflammasome. J Immunol. 2020; 204(6): 1448–1461.
  16. Zhao J, Zhang H, Huang Y, et al. Bay11-7082 attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation. Int Immunopharmacol. 2013; 17(1): 116–122.
  17. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol. 2002; 2(10): 725–734.
  18. Williams LM, Gilmore TD. Looking down on NF-κB. Mol Cell Biol. 2020; 40(15).
  19. Zheng L, Sinniah R, Hsu SIH. Pathogenic role of NF-kappaB activation in tubulointerstitial inflammatory lesions in human lupus nephritis. J Histochem Cytochem. 2008; 56(5): 517–529.
  20. Li X, Wang M, Hong H, et al. Sophocarpine attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation. Immunol Res. 2018; 66(4): 521–527.
  21. Su B, Ye H, You X, et al. Icariin alleviates murine lupus nephritis via inhibiting NF-κB activation pathway and NLRP3 inflammasome. Life Sci. 2018; 208: 26–32.
  22. Tao X, Yin L, Xu L, et al. Dioscin: A diverse acting natural compound with therapeutic potential in metabolic diseases, cancer, inflammation and infections. Pharmacol Res. 2018; 137: 259–269.
  23. Qi M, Zheng L, Qi Y, et al. Dioscin attenuates renal ischemia/reperfusion injury by inhibiting the TLR4/MyD88 signaling pathway via up-regulation of HSP70. Pharmacol Res. 2015; 100: 341–352.
  24. Wang Y, Liu P, Ma G, et al. Mechanism of dioscin ameliorating renal fibrosis through NF‑κB signaling pathway‑mediated inflammatory response. Mol Med Rep. 2023; 27(4).
  25. Cai S, Chen J, Li Y. Dioscin protects against diabetic nephropathy by inhibiting renal inflammation through TLR4/NF-κB pathway in mice. Immunobiology. 2020; 225(3): 151941.
  26. Zhang P, Lei X, Ou L, et al. Dioscin ameliorates silica-aggravated systemic lupus erythematosus via suppressing apoptosis and improving LC3-associated phagocytosis in MRL/lpr mice. Int Immunopharmacol. 2023; 116: 109814.
  27. Jiang X, Ding X, Wei J, et al. Dioscin alleviates periodontitis by inhibiting NLRP3 inflammasome activation via regulation of k homeostasis and mitochondrial function. Int J Biol Sci. 2024; 20(4): 1375–1388.
  28. Liang CL, Lu W, Qiu F, et al. Paeoniflorin ameliorates murine lupus nephritis by increasing CD4Foxp3 Treg cells via enhancing mTNFα-TNFR2 pathway. Biochem Pharmacol. 2021; 185: 114434.
  29. Qi Q, Li H, Lin ZM, et al. (5R)-5-hydroxytriptolide ameliorates anti-glomerular basement membrane glomerulonephritis in NZW mice by regulating Fcγ receptor signaling. Acta Pharmacol Sin. 2018; 39(1): 107–116.
  30. Jia Y, He J, Wang L, et al. Dapagliflozin aggravates renal injury via promoting gluconeogenesis in db/db mice. Cell Physiol Biochem. 2018; 45(5): 1747–1758.
  31. Kökény G, Fang L, Révész C, et al. The Effect of Combined Treatment with the (Pro)Renin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats. Kidney Blood Press Res. 2017; 42(1): 109–122.
  32. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25(4): 402–408.
  33. Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol. 2016; 68(6): 1432–1441.
  34. Qiao Y, Xu L, Tao X, et al. Protective effects of dioscin against fructose-induced renal damage via adjusting Sirt3-mediated oxidative stress, fibrosis, lipid metabolism and inflammation. Toxicol Lett. 2018; 284: 37–45.
  35. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011; 365(22): 2110–2121.
  36. Richoz N, Tuong ZK, Loudon KW, et al. Distinct pathogenic roles for resident and monocyte-derived macrophages in lupus nephritis. JCI Insight. 2022; 7(21).
  37. Ma C, Xia Yu, Yang Q, et al. The contribution of macrophages to systemic lupus erythematosus. Clin Immunol. 2019; 207: 1–9.
  38. Kurts C, Panzer U, Anders HJ, et al. The immune system and kidney disease: basic concepts and clinical implications. Nat Rev Immunol. 2013; 13(10): 738–753.
  39. Lin L, Shen J, Wu X, et al. Dioscin mediated IgA nephropathy alleviation by inhibiting B cell activation in vivo and decreasing galactose-deficient IgA1 production in vitro. J Vis Exp. 2023(200).
  40. Wu MM, Wang QM, Huang BY, et al. Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization. Pharmacol Res. 2021; 172: 105796.
  41. Shi L, Zhang P, Jin R, et al. Dioscin ameliorates inflammatory bowel disease by up-regulating miR-125a-5p to regulate macrophage polarization. J Clin Lab Anal. 2022; 36(6): e24455.
  42. Li C, Lu Y, Du S, et al. Dioscin exerts protective effects against crystalline silica-induced pulmonary fibrosis in mice. Theranostics. 2017; 7(17): 4255–4275.
  43. Kahlenberg JM, Carmona-Rivera C, Smith CK, et al. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages. J Immunol. 2013; 190(3): 1217–1226.
  44. Liu X, Bao C, Hu D. Elevated interleukin-18 and skewed Th1:Th2 immune response in lupus nephritis. Rheumatol Int. 2012; 32(1): 223–229.
  45. Ding Yi, Chen Q. The NF-κB Pathway: a Focus on Inflammatory Responses in Spinal Cord Injury. Mol Neurobiol. 2023; 60(9): 5292–5308.
  46. Han J, Shi G, Li W, et al. Preventive effect of dioscin against monosodium urate-mediated gouty arthritis through inhibiting inflammasome NLRP3 and TLR4/NF-κB signaling pathway activation: an in vivo and in vitro study. J Nat Med. 2021; 75(1): 37–47.
  47. Ran X, Yan Z, Yang Y, et al. Dioscin improves pyroptosis in LPS-induced mice mastitis by activating AMPK/Nrf2 and inhibiting the NF-κB signaling pathway. Oxid Med Cell Longev. 2020; 2020: 8845521.
  48. Cai J, Liu J, Fan P, et al. Dioscin prevents DSS-induced colitis in mice with enhancing intestinal barrier function and reducing colon inflammation. Int Immunopharmacol. 2021; 99: 108015.
  49. Lu Z, Yao Y, Wang J, et al. Dioscin ameliorates diabetes cognitive dysfunction via adjusting P2X7R/NLRP3 signal. Int Immunopharmacol. 2021; 101(Pt B): 108314.
  50. Qi M, Yin L, Xu L, et al. Dioscin alleviates lipopolysaccharide-induced inflammatory kidney injury via the microRNA let-7i/TLR4/MyD88 signaling pathway. Pharmacol Res. 2016; 111: 509–522.
  51. Perry D, Sang A, Yin Y, et al. Murine models of systemic lupus erythematosus. J Biomed Biotechnol. 2011; 2011: 271694.