Vol 62, No 1 (2024)
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Published online: 2024-04-02

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Nephroprotective effect of Ginsenoside Rg1 in lipopolysaccharide-induced sepsis in mice through the SIRT1/NF-κB signaling

Yadan Hu1, Chao Xiang2, Dong Zhang1, Fang Zhou1, Dede Zhang1
Pubmed: 38563049
Folia Histochem Cytobiol 2024;62(1):13-24.

Abstract

Introduction. During sepsis, the kidney is one of the most vulnerable organs. Sepsis-associated acute kidney injury (S-AKI) is hallmarked by renal inflammation, apoptosis, and oxidative injury. Ginsenoside Rg1 (Rg1) is a natural product that possesses abundant pharmacological actions and protects against many sepsis-related diseases. Nevertheless, its role and related mechanism in S-AKI remain to be determined.

Materials and methods. S-AKI was induced using lipopolysaccharide (LPS, 10 mg/kg) via a single intraperitoneal injection. Rg1 (200 mg/kg) was intraperitoneally administered for 3 consecutive days before LPS treatment. For histopathological examination, murine kidney tissues were stained with hematoxylin and eosin. Tubular injury score was calculated to evaluate kidney injury. Serum creatinine and BUN levels were measured for assessing renal dysfunction. The levels and activities of oxidative stress markers (MDA, 4-HNE, PC, GSH, SOD, and CAT) in renal tissue were measured by corresponding kits. Renal cell apoptosis was detected by TUNEL staining. The protein levels of apoptosis-related markers (Bcl-2, Bax, and Cleaved caspase-3), proinflammatory factors, SIRT1, IκBα, p-NF-κB p65, and NF-κB p65 in kidneys were determined using western blotting. Immunofluorescence staining was employed to assess p-NF-κB p65 expression in renal tissues.

Results. LPS-induced injury of kidneys and renal dysfunction in mice were ameliorated by Rg1. Rg1 also impeded LPS-evoked renal cell apoptosis in kidneys. Moreover, Rg1 attenuated LPS-triggered inflammation and oxidative stress in kidneys by inhibiting proinflammatory cytokine release, enhancing antioxidant levels and activities, and reducing lipid peroxidation. However, all these protective effects of Rg1 in LPS-induced AKI mice were reversed by EX527, an inhibitor of sirtuin 1 (SIRT1). Mechanistically, Rg1 upregulated SIRT1 protein expression, increased SIRT1 activity, and inactivated NF-κB signaling in the kidney of LPS-induced AKI mice, which was also reversed by EX527.

Conclusions. Rg1 ameliorates LPS-induced kidney injury and suppresses renal inflammation, apoptosis, and oxidative
stress in mice via regulating the SIRT1/NF-κB signaling.

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References

  1. Uhle F, Lichtenstern C, Brenner T, et al. Pathophysiology of sepsis. Anasthesiol Intensivmed Notfallmed Schmerzther. 2015; 50(2): 114–122.
  2. Poston JT, Koyner JL. Sepsis associated acute kidney injury. BMJ. 2019; 364: k4891.
  3. Peerapornratana S, Manrique-Caballero CL, Gómez H, et al. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 2019; 96(5): 1083–1099.
  4. Manrique-Caballero CL, Del Rio-Pertuz G, Gomez H. Sepsis-associated acute kidney injury. Crit Care Clin. 2021; 37(2): 279–301.
  5. Gomez H, Ince C, De Backer D, et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock. 2014; 41(1): 3–11.
  6. Stasi A, Intini A, Divella C, et al. Emerging role of Lipopolysaccharide binding protein in sepsis-induced acute kidney injury. Nephrol Dial Transplant. 2017; 32(1): 24–31.
  7. Wang Z, Wu J, Hu Z, et al. Dexmedetomidine alleviates lipopolysaccharide-induced acute kidney injury by inhibiting p75NTR-Mediated oxidative stress and apoptosis. Oxid Med Cell Longev. 2020; 2020: 5454210.
  8. Yoo JY, Cha DR, Kim B, et al. LPS-Induced acute kidney injury is mediated by Nox4-SH3YL1. Cell Rep. 2020; 33(3): 108245.
  9. Huang G, Bao J, Shao X, et al. Inhibiting pannexin-1 alleviates sepsis-induced acute kidney injury via decreasing NLRP3 inflammasome activation and cell apoptosis. Life Sci. 2020; 254: 117791.
  10. Chen J, Zhang X, Liu X, et al. Ginsenoside Rg1 promotes cerebral angiogenesis via the PI3K/Akt/mTOR signaling pathway in ischemic mice. Eur J Pharmacol. 2019; 856: 172418.
  11. Zou Y, Tao T, Tian Ye, et al. Ginsenoside Rg1 improves survival in a murine model of polymicrobial sepsis by suppressing the inflammatory response and apoptosis of lymphocytes. J Surg Res. 2013; 183(2): 760–766.
  12. Mei X, Feng H, Shao B. Alleviation of sepsis-associated encephalopathy by ginsenoside via inhibition of oxidative stress and cell apoptosis: An experimental study. Pak J Pharm Sci. 2020; 33(6): 2567–2577.
  13. Luo M, Yan D, Sun Q, et al. Ginsenoside Rg1 attenuates cardiomyocyte apoptosis and inflammation via the TLR4/NF-kB/NLRP3 pathway. J Cell Biochem. 2020; 121(4): 2994–3004.
  14. Mao N, Tan RZ, Wang SQ, et al. Ginsenoside Rg1 inhibits angiotensin II-induced podocyte autophagy via AMPK/mTOR/PI3K pathway. Cell Biol Int. 2016; 40(8): 917–925.
  15. Guo X, Zhang J, Liu M, et al. Protective effect of ginsenoside Rg1 on attenuating anti-GBM glomerular nephritis by activating NRF2 signalling. Artif Cells Nanomed Biotechnol. 2019; 47(1): 2972–2979.
  16. Shen X, Dong X, Han Y, et al. Ginsenoside Rg1 ameliorates glomerular fibrosis during kidney aging by inhibiting NOX4 and NLRP3 inflammasome activation in SAMP8 mice. Int Immunopharmacol. 2020 [Epub ahead of print]; 82: 106339.
  17. Chen C, Zhou M, Ge Y, et al. SIRT1 and aging related signaling pathways. Mech Ageing Dev. 2020; 187: 111215.
  18. Wei S, Gao Y, Dai X, et al. SIRT1-mediated HMGB1 deacetylation suppresses sepsis-associated acute kidney injury. Am J Physiol Renal Physiol. 2019; 316(1): F20–F31.
  19. Li Lu, Liu X, Li S, et al. Tetrahydrocurcumin protects against sepsis-induced acute kidney injury via the SIRT1 pathway. Ren Fail. 2021; 43(1): 1028–1040.
  20. Kauppinen A, Suuronen T, Ojala J, et al. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cellular Signalling. 2013; 25(10): 1939–1948.
  21. DiDonato JA, Mercurio F, Karin M. NF-κB and the link between inflammation and cancer. Immunol Rev. 2012; 246(1): 379–400.
  22. Lu S, Zhou S, Chen J, et al. Quercetin nanoparticle ameliorates lipopolysaccharide-triggered renal inflammatory impairment by regulation of sirt1/nf-kb pathway. J Biomed Nanotechnol. 2021; 17(2): 230–241.
  23. Wang QL, Yang L, Peng Y, et al. Ginsenoside Rg1 Regulates SIRT1 to Ameliorate Sepsis-Induced Lung Inflammation and Injury via Inhibiting Endoplasmic Reticulum Stress and Inflammation. Mediators Inflamm. 2019; 2019: 6453296.
  24. Nadeem A, Ahmad SF, Al-Harbi NO, et al. Role of ITK signaling in acute kidney injury in mice: amelioration of acute kidney injury associated clinical parameters and attenuation of inflammatory transcription factor signaling in CD4+ T cells by ITK inhibition. Int Immunopharmacol. 2021; 99: 108028.
  25. Wang XY, Li XY, Wu CH, et al. Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis. Respir Res. 2021; 22(1): 193.
  26. Li Y, Wang F, Luo Y. Ginsenoside Rg1 protects against sepsis-associated encephalopathy through beclin 1-independent autophagy in mice. J Surg Res. 2017; 207: 181–189.
  27. Shen Y, Qiu T, Liu XH, et al. Renal ischemia-reperfusion injury attenuated by splenic ischemic preconditioning. Eur Rev Med Pharmacol Sci. 2018; 22(7): 2134–2142.
  28. Zhao X, Wang M, Sun Z, et al. MicroRNA-139-5p improves sepsis-induced lung injury by targeting Rho-kinase1. Exp Ther Med. 2021; 22(4): 1059.
  29. Jensen EC. Quantitative analysis of histological staining and fluorescence using ImageJ. Anat Rec (Hoboken). 2013; 296(3): 378–381.
  30. Pan T, Jia P, Chen N, et al. Delayed remote ischemic preconditioning confersrenoprotection against septic acute kidney injury via exosomal miR-21. Theranostics. 2019; 9(2): 405–423.
  31. Xia S, Lin H, Liu H, et al. Honokiol attenuates sepsis-associated acute kidney injury via the inhibition of oxidative stress and inflammation. Inflammation. 2019; 42(3): 826–834.
  32. Wang Y, Feng F, Liu M, et al. Resveratrol ameliorates sepsis-induced acute kidney injury in a pediatric rat model via Nrf2 signaling pathway. Exp Ther Med. 2018; 16(4): 3233–3240.
  33. Zhang B, Xue Yi, Zhao J, et al. Shionone attenuates sepsis-induced acute kidney injury by regulating macrophage polarization the ECM1/STAT5 pathway. Front Med (Lausanne). 2021; 8: 796743.
  34. Xu X, Qu Z, Qian H, et al. Ginsenoside Rg1 ameliorates reproductive function injury in C57BL/6J mice induced by di-N-butyl-phthalate. Environ Toxicol. 2021; 36(5): 789–799.
  35. Su F, Xue Y, Wang Y, et al. Protective effect of ginsenosides Rg1 and Re on lipopolysaccharide-induced sepsis by competitive binding to Toll-like receptor 4. Antimicrob Agents Chemother. 2015; 59(9): 5654–5663.
  36. Zhang ZB, Xu QP. Experimental study of ginsenoside Rg1 combined with antibiotics in the treatment of acute lung injury in mice with sepsis. Sichuan Da Xue Xue Bao Yi Xue Ban. 2020; 51(3): 371–375.
  37. Liu Z, Pan H, Zhang Y, et al. Ginsenoside-Rg1 attenuates sepsis-induced cardiac dysfunction by modulating mitochondrial damage via the P2X7 receptor-mediated Akt/GSK-3β signaling pathway. J Biochem Mol Toxicol. 2022; 36(1): e22885.
  38. Chen Y, Chi M, Qiao X, et al. Anti-inflammatory effect of ginsenoside Rg1 on LPS-induced septic encephalopathy and associated mechanism. Curr Neurovasc Res. 2022; 19(1): 38–46.
  39. Li SS, He AL, Deng ZY, et al. Ginsenoside-Rg1 protects against renal fibrosis by regulating the klotho/tTGF-β1/Smad signaling pathway in rats with obstructive nephropathy. Biol Pharm Bull. 2018; 41(4): 585–591.
  40. Xie XS, Yang M, Liu HC, et al. Influence of ginsenoside Rg1, a panaxatriol saponin from Panax notoginseng, on renal fibrosis in rats with unilateral ureteral obstruction. J Zhejiang Univ Sci B. 2008; 9(11): 885–894.
  41. Zhang D, Ji P, Sun R, et al. Ginsenoside Rg1 attenuates LPS-induced chronic renal injury by inhibiting NOX4-NLRP3 signaling in mice. Biomed Pharmacother. 2022; 150: 112936.
  42. Shimokawa T, Yoneda K, Yamagata M, et al. Yohimbine ameliorates lipopolysaccharide-induced acute kidney injury in rats. Eur J Pharmacol. 2020; 871: 172917.
  43. Qi SS, Zheng HX, Jiang H, et al. Protective effects of chromium picolinate against diabetic-induced renal dysfunction and renal fibrosis in streptozotocin-induced diabetic rats. Biomolecules. 2020; 10(3).
  44. Li SS, Ye Jm, Deng Zy, et al. Ginsenoside-Rg1 inhibits endoplasmic reticulum stress-induced apoptosis after unilateral ureteral obstruction in rats. Ren Fail. 2015; 37(5): 890–895.
  45. Xu HP, Ma XY, Yang C. Circular RNA TLK1 promotes sepsis-associated acute kidney injury by regulating inflammation and oxidative stress through miR-106a-5p/HMGB1 axis. Front Mol Biosci. 2021; 8: 660269.
  46. Ow CPC, Trask-Marino A, Betrie AH, et al. Targeting oxidative stress in septic acute kidney injury: from theory to practice. J Clin Med. 2021; 10(17).
  47. Pavlakou P, Liakopoulos V, Eleftheriadis T, et al. Oxidative Stress and Acute Kidney Injury in Critical Illness: Pathophysiologic Mechanisms-Biomarkers-Interventions, and Future Perspectives. Oxid Med Cell Longev. 2017; 2017: 6193694.
  48. Gui Y, Yang Y, Xu D, et al. Schisantherin A attenuates sepsis-induced acute kidney injury by suppressing inflammation via regulating the NRF2 pathway. Life Sci. 2020; 258: 118161.
  49. Zhang J, Yue Y, Ma Y. Ameliorates sepsis-induced acute kidney injury in mice by promoting CXCL14. Allergol Immunopathol (Madr). 2022; 50(6): 187–194.
  50. Liu X, Lu J, Liao Y, et al. Dihydroartemisinin attenuates lipopolysaccharide-induced acute kidney injury by inhibiting inflammation and oxidative stress. Biomed Pharmacother. 2019; 117: 109070.
  51. Wang Li, Mao N, Tan RZ, et al. Ginsenoside Rg1 reduces aldosterone-induced autophagy via the AMPK/mTOR pathway in NRK-52E cells. Int J Mol Med. 2015; 36(2): 518–526.
  52. Du Na, Xu Z, Gao M, et al. Combination of Ginsenoside Rg1 and Astragaloside IV reduces oxidative stress and inhibits TGF-β1/Smads signaling cascade on renal fibrosis in rats with diabetic nephropathy. Drug Des Devel Ther. 2018; 12: 3517–3524.
  53. Gu L, Liu J, Xu D, et al. Polydatin prevents LPS-induced acute kidney injury through inhibiting inflammatory and oxidative responses. Microb Pathog. 2019; 137: 103688.
  54. Wu TJ, Hsieh YJ, Lu CW, et al. Linagliptin protects against endotoxin-induced acute kidney injury in rats by decreasing inflammatory cytokines and reactive oxygen species. Int J Mol Sci. 2021; 22(20).
  55. Ren TT, Yang JY, Wang J, et al. Gisenoside Rg1 attenuates cadmium-induced neurotoxicity in vitro and in vivo by attenuating oxidative stress and inflammation. Inflamm Res. 2021; 70(10-12): 1151–1164.
  56. Zhan Y, Zhu M, Liu S, et al. MicroRNA‑93 inhibits the apoptosis and inflammatory response of tubular epithelial cells via the PTEN/AKT/mTOR pathway in acute kidney injury. Mol Med Rep. 2021; 24(3).
  57. Wang Bo, Xu J, Ren Q, et al. Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis. Cell Death Dis. 2022; 13(4): 333.
  58. Plotnikov EY, Brezgunova AA, Pevzner IB, et al. Mechanisms of LPS-induced acute kidney injury in neonatal and adult rats. Antioxidants (Basel). 2018; 7(8).
  59. Zhu MX, Ran B, Feng ZQ, et al. Effects of Rb1 and Rg1 on the expression of Bcl-2, Bax in apoptosis of HK-2 cells induced by the serum of kidney ischemia/reperfusion. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2009; 25(4): 496–499.
  60. Ji QJ, Sun ZR, Yang ZZ, et al. Protective effect of ginsenoside Rg1 on LPS-induced apoptosis of lung epithelial cells. Mol Immunol. 2021; 136(8): 168–174.
  61. Liu QF, Deng ZY, Ye JM, et al. Ginsenoside Rg1 protects chronic cyclosporin a nephropathy from tubular cell apoptosis by inhibiting endoplasmic reticulum stress in rats. Transplant Proc. 2015; 47(2): 566–569.
  62. Yang Y, Liu Y, Wang Y, et al. The roles of CCR9/CCL25 in inflammation and inflammation-associated diseases. Front Cell Dev Biol. 2021; 9: 686548.
  63. You Y, Liang W. SIRT1 and SIRT6: The role in aging-related diseases. Biochim Biophys Acta Mol Basis Dis. 2023; 1869(7): 166815.
  64. Deng Z, Sun M, Wu J, et al. SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation. Cell Death Dis. 2021; 12(2): 217.
  65. Guo J, Wang R, Liu D. Bone marrow-derived mesenchymal stem cells ameliorate sepsis-induced acute kidney injury by promoting mitophagy of renal tubular epithelial cells the sirt1/parkin axis. Front Endocrinol (Lausanne). 2021; 12: 639165.
  66. Liu P, Shi D. Calcitonin gene-related peptide attenuates LPS-induced acute kidney injury by regulating Sirt1. Med Sci Monit. 2020; 26: e923900.
  67. Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009; 1(6): a001651.
  68. Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011; 12(8): 695–708.
  69. Chen Y, Zhang Q, Sun L, et al. Ginsenoside Rg1 attenuates dextran sodium sulfate-induced ulcerative colitis in mice. Physiol Res. 2023; 72(6): 783–792.
  70. Xiao Q, Zhang S, Yang C, et al. Ginsenoside Rg1 ameliorates palmitic acid-induced hepatic steatosis and inflammation in HepG2 cells via the AMPK/NF-B pathway. Int J Endocrinol. 2019; 2019: 7514802.
  71. Wu Z, Chen J, Zhao W, et al. Inhibition of miR-181a attenuates sepsis-induced inflammation and apoptosis by activating Nrf2 and inhibiting NF-κB pathways via targeting SIRT1. Kaohsiung J Med Sci. 2021; 37(3): 200–207.
  72. Yang Y, Liu Y, He X, et al. ING4 alleviated lipopolysaccharide-induced inflammation by regulating the NF-κB pathway via a direct interaction with SIRT1. Immunol Cell Biol. 2020; 98(2): 127–137.



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