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CTLA4-Ig protects tacrolimus-induced oxidative stress via inhibiting the AKT/FOXO3 signaling pathway in rats

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Background/Aims: Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress. Methods: In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2’-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1). Results: CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF- 1 treatment abolished the effects of CTLA4-Ig. Conclusions: CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

Abstract

Background/Aims: Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress. Methods: In vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2’-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1). Results: CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF- 1 treatment abolished the effects of CTLA4-Ig. Conclusions: CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

참고문헌 (52)

  1. Li L, "Clinical transplants 2006" (2006), Terasaki Research Institute
  2. Tomasoni S, "Allograft rejection : acute and chronic studies", Contrib Nephrol, 159, pp.122~134 (2008)
  3. Miano TA, "Early tacrolimus concentrations after lung transplant are predicted by combined clinical and genetic factors and associated with acute kidney injury", Clin Pharmacol Ther, 107, pp.462~470 (2020)
  4. Braithwaite HE, "Identifying the association between tacrolimus exposure and toxicity in heart and lung transplant recipients: a systematic review", Transplant Rev(Orlando), 35, pp.100610~ (2021)
  5. Lim SW, "Effect of Klotho on autophagy clearance in tacrolimus-induced renal injury", FASEB J, 33, pp.2694~2706 (2019)
  6. Lim SW, "Inhibition of dipeptidyl peptidase IV protects tacrolimus-induced kidney injury", Lab Invest, 95, pp.1174~1185 (2015)
  7. 이다혜, "Protective effect of ginsenoside Rb1 against tacrolimus-induced apoptosis in renal proximal tubular LLC-PK1 cells", Journal of Ginseng Research, 42(1), pp.75~80 (2018), 고려인삼학회[DOI]
  8. Greenfield EA, "CD28", B7 costimulation : a review, 1998, pp.18, 389~418
  9. Pilat N, "CTLA4Ig improves murine iTreg induction via TGFβ and suppressor function in vitro", J Immunol Res, 2018, pp.2484825~ (2018)
  10. Jaiswal SR, "CTLA4Ig in an extended schedule along with sirolimus improves outcome with a distinct pattern of immune reconstitution following post-transplantation cyclophosphamide-based haploidentical transplantation for hemoglobinopathies", Biol Blood Marrow Transplant, 26, pp.1469~1476 (2020)
  11. Kumar D, "Belatacept as an alternative to calcineurin inhibitors in patients with solid organ transplants", Front Med(Lausanne), 4, pp.60~ (2017)
  12. Jin L, "Effect of conversion to CTLA4Ig on tacrolimus-induced diabetic rats", Transplantation, 102, pp.e137~e146 (2018)
  13. Wang Y, "TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K", AKT, Aging(Albany NY), pp.2020, 12[DOI]
  14. Zhang X, "Dihydromyricetin protects HUVECs of oxidative damage induced by sodium nitroprusside through activating PI3K", Akt, J Cell Mol Med, pp.2019, 23[DOI]
  15. 윤혜은, "Tempol Attenuates Renal Fibrosis in Mice with Unilateral Ureteral Obstruction: The Role of PI3K–Akt–FoxO3a Signaling", Journal of Korean Medical Science, 29(2), pp.230~237 (2014), 대한의학회
  16. Zhao S, "Inhibitor of growth 3 induces cell death by regulating cell proliferation, apoptosis and cell cycle arrest by blocking the PI3K", AKT pathway, 2018, pp.25, 240~247
  17. Jin L, "Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats", PLoS One, 9, pp.e100798~ (2014)
  18. Chevalier RL, "Renal tubulointerstitial injury from ureteral obstruction in the neonatal rat is attenuated by IGF-1", Kidney Int, 57, pp.882~890 (2000)
  19. Haffner D, "Renal effects of growth hormone in health and in kidney disease", Pediatr Nephrol, 36, pp.2511~2530 (2021)
  20. Fu R, "Establishment of an experimental rat model of tacrolimus-induced kidney injury accompanied by interstitial fibrosis", Toxicol Lett, 341, pp.43~50 (2021)
  21. Yu Ji Jiang, "Nicotine exacerbates tacrolimus-induced renal injury by programmed cell death", The Korean Journal of Internal Medicine, 36(6), pp.1437~1449 (2021), 대한내과학회[DOI]
  22. Jin J, "Effect of empagliflozin on tacrolimus-induced pancreas islet dysfunction and renal injury", Am J Transplant, 17, pp.2601~2616 (2017)
  23. Yang CC, "Combined tacrolimus and melatonin effectively protected kidney against acute ischemia-reperfusion injury", FASEB J, 35, pp.e21661~ (2021)
  24. Piao SG, "Combined treatment of tacrolimus and everolimus increases oxidative stress by pharmacological interactions", Transplantation, 98, pp.22~28 (2014)
  25. Chen Y, "Dexmedetomidine ameliorates acute stress-induced kidney injury by attenuating oxidative stress and apoptosis through inhibition of the ROS", JNK signaling pathway, 2018, pp.2018, 4035310~
  26. García-Pérez E, "Human proximal tubule epithelial cells(HK-2)as a sensitive in vitro system for ochratoxin a induced oxidative stress", Toxins(Basel), 13, pp.787~ (2021)
  27. Wang YL, "The kidney-related effects of polystyrene microplastics on human kidney proximal tubular epithelial cells HK-2 and male C57BL", 6 mice, 2021, pp.129, 57003~
  28. Gao P, "Astragaloside IV alleviates tacrolimus-induced chronic nephrotoxicity via p62-Keap1-Nrf2 pathway", Front Pharmacol, 11, pp.610102~ (2021)
  29. Zheng HL, "L-Carnitine protects against tacrolimus-induced renal injury by attenuating programmed cell death via PI3K", AKT, Acta Pharmacol Sin, pp.2021, 42[DOI]
  30. Guerrieri D, "Secretory leukocyte proteinase inhibitor protects acute kidney injury through immune and non-immune pathways", Shock, 56, pp.1019~1027 (2021)
  31. Tzivion G, "FoxO transcription factors; regulation by AKT and 14-3-3 proteins", Biochim Biophys Acta, 1813, pp.1938~1945 (2011)
  32. Kurosu H, "Suppression of aging in mice by the hormone Klotho", Science, 309, pp.1829~1833 (2005)
  33. Yamamoto M, "Regulation of oxidative stress by the anti-aging hormone klotho", J Biol Chem, 280, pp.38029~38034 (2005)
  34. Unger RH, "Klotho-induced insulin resistance : a blessing in disguise?", Nat Med, 12, pp.56~57 (2006)
  35. Emerling BM, "PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through forkhead transcription factor 3a(FOXO3a)", Proc Natl Acad Sci U S A, 105, pp.2622~2627 (2008)
  36. Lim SW, "Klotho enhances FoxO3-mediated manganese superoxide dismutase expression by negatively regulating PI3K", AKT pathway during tacrolimus-induced oxidative stress, 2017, pp.8, e2972~
  37. Reyes HD, "Downregulation of FOXO1 mRNA levels predicts treatment failure in patients with endometrial pathology conservatively managed with progestin-containing intrauterine devices", Gynecol Oncol, 140, pp.152~160 (2016)
  38. Du M, "Overexpression of FOXO1 ameliorates the podocyte epithelial-mesenchymal transition induced by high glucose in vitro and in vivo", Biochem Biophys Res Commun, 471, pp.416~422 (2016)
  39. Li W, "Effects of overexpressing FoxO1on apoptosis in glomeruli of diabetic mice and in podocytes cultured in high glucose medium", Biochem Biophys Res Commun, 478, pp.612~617 (2016)
  40. Fallarino F, "CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice", J Exp Med, 200, pp.1051~1062 (2004)
  41. Del Rio D, "A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress", Nutr Metab Cardiovasc Dis, 15, pp.316~328 (2005)
  42. Graille M, "Urinary 8-OHdG as a biomarker for oxidative stress : a systematic literature review and meta-analysis", Int J Mol Sci, 21, pp.3743~ (2020)
  43. Soulage CO, "Two toxic lipid aldehydes, 4-hydroxy-2-hexenal(4-HHE)and 4-hydroxy-2-nonenal(4-HNE), accumulate in patients with chronic kidney disease", Toxins(Basel), 12, pp.567~ (2020)
  44. Saeki T, "Expression of oxidative stress-related molecules in circulating leukocytes and urine in patients with chronic viral hepatitis", Liver Int, 26, pp.157~165 (2006)
  45. Homma T, "Application of glutathione as anti-oxidative and anti-aging drugs", Curr Drug Metab, 16, pp.560~571 (2015)
  46. Couto N, "The role of glutathione reductase and related enzymes on cellular redox homoeostasis network", Free Radic Biol Med, 95, pp.27~42 (2016)
  47. Kim JL, "Pegylated-catalase is protective in lung ischemic injury and oxidative stress", Ann Thorac Surg, 111, pp.1019~1027 (2021)
  48. Tahir M, "Heavy metal-associated oxidative stress and glutathione S-transferase polymorphisms among E-waste workers in Pakistan", Environ Geochem Health, 43, pp.4441~4458 (2021)
  49. Qin G, "Overexpression of the FoxO1ameliorates mesangial cell dysfunction in male diabetic rats", Mol Endocrinol, 29, pp.1080~1091 (2015)
  50. Dávila D, "Neuronal death by oxidative stress involves activation of FOXO3 through a two-arm pathway that activates stress kinases and attenuates insulin-like growth factor I signaling", Mol Biol Cell, 19, pp.2014~2025 (2008)
  51. Genis L, "Astrocytes require insulin-like growth factor I to protect neurons against oxidative injury", F1000Res, 3, pp.28~ (2014)
  52. Lehtinen MK, "A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span", Cell, 125, pp.987~1001 (2006)

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