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Akt1 is involved in tubular apoptosis and inflammatory response during renal ischemia–reperfusion injury

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Abstract

Renal ischemia–reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI). Although Akt is involved in renal IRI, it is unclear as to which Akt isoform plays an important role in renal IRI. In this study, we investigated the role of Akt1 in renal IRI. We subjected the C57BL/6 male mice to unilateral IRI with contralateral nephrectomy. Two days after IRI, IRI-kidneys were harvested. The mice were divided into four groups: wild type (WT) IRI, Akt1−/− IRI, WT sham, and Akt1−/− sham. We found that Akt1, not Akt2 or Akt3, was markedly activated in WT IRI than in WT sham mice. The histologic damage score and serum creatinine level significantly increased in WT IRI mice, the increase being the highest in Akt1−/− IRI mice. The number of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells and expression of cleaved caspase-3/Bax were higher in Akt1−/− IRI mice than in WT IRI mice. The expression of Bcl-2 was lower in Akt1−/− IRI mice than in WT IRI mice. The expression of tumor necrosis factor-α/interleukin-6/interleukin-1β and number of F4/80-positive macrophages were markedly higher in Akt1−/− IRI than in WT IRI mice. The expression of phosphorylated nuclear factor-κB p65 was also higher in Akt1−/− IRI mice than in WT IRI mice. Our results show that Akt1 deletion exacerbates kidney damage as it increases tubular apoptosis and inflammatory response during renal IRI. Akt1 could be a potential therapeutic target for developing treatments against IRI-induced AKI.

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References

  1. Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu CY (2013) Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol 24:37–42. https://doi.org/10.1681/ASN.2012080800

    Article  PubMed  Google Scholar 

  2. Basile DP, Yoder MC (2014) Renal endothelial dysfunction in acute kidney ischemia reperfusion injury. Cardiovasc Hematol Disord Drug Targets 14:3–14. https://doi.org/10.2174/1871529x1401140724093505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xie DQ, Sun GY, Zhang XG, Gan H (2015) Osthole preconditioning protects rats against renal ischemia-reperfusion injury. Transplant Proc 47:1620–1626. https://doi.org/10.1016/j.transproceed.2015.06.011

    Article  CAS  PubMed  Google Scholar 

  4. Kusch A, Hoff U, Bubalo G, Zhu Y, Fechner M, Schmidt-Ullrich R, Marko L, Muller DN, Schmidt-Ott KM, Gurgen D, Blum M, Schunck WH, Dragun D (2013) Novel signalling mechanisms and targets in renal ischaemia and reperfusion injury. Acta Physiol (Oxf) 208:25–40. https://doi.org/10.1111/apha.12089

    Article  CAS  Google Scholar 

  5. Yang FJ, He YH, Zhou JH (2015) Fenofibrate pre-treatment suppressed inflammation by activating phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) signaling in renal ischemia-reperfusion injury. J Huazhong Univ Sci Technol Med Sci 35:58–63. https://doi.org/10.1007/s11596-015-1389-2

    Article  CAS  Google Scholar 

  6. Lien YH, Lai LW, Silva AL (2003) Pathogenesis of renal ischemia/reperfusion injury: lessons from knockout mice. Life Sci 74:543–552. https://doi.org/10.1016/j.lfs.2003.08.001

    Article  CAS  PubMed  Google Scholar 

  7. Zhang J, Zou YR, Zhong X, Deng HD, Pu L, Peng K, Wang L (2015) Erythropoietin pretreatment ameliorates renal ischaemia-reperfusion injury by activating PI3K/Akt signalling. Nephrology (Carlton) 20:266–272. https://doi.org/10.1111/nep.12384

    Article  CAS  Google Scholar 

  8. Amura CR, Renner B, Lyubchenko T, Faubel S, Simonian PL, Thurman JM (2012) Complement activation and toll-like receptor-2 signaling contribute to cytokine production after renal ischemia/reperfusion. Mol Immunol 52:249–257. https://doi.org/10.1016/j.molimm.2012.05.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang C, Zhao T, Lin M, Zhao Z, Hu L, Jia Y, Xue Y, Xu M, Tang Q, Yang B, Rong R, Zhu T (2013) Helix B surface peptide administered after insult of ischemia reperfusion improved renal function, structure and apoptosis through beta common receptor/erythropoietin receptor and PI3K/Akt pathway in a murine model. Exp Biol Med (Maywood) 238:111–119. https://doi.org/10.1258/ebm.2012.012185

    Article  CAS  Google Scholar 

  10. Lan A, Du J (2015) Potential role of Akt signaling in chronic kidney disease. Nephrol Dial Transplant 30:385–394. https://doi.org/10.1093/ndt/gfu196

    Article  CAS  PubMed  Google Scholar 

  11. Yu H, Littlewood T, Bennett M (2015) Akt isoforms in vascular disease. Vascul Pharmacol 71:57–64. https://doi.org/10.1016/j.vph.2015.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xie L, Zheng X, Qin J, Chen Z, Jin Y, Ding W (2006) Role of PI3-kinase/Akt signalling pathway in renal function and cell proliferation after renal ischaemia/reperfusion injury in mice. Nephrology (Carlton) 11:207–212. https://doi.org/10.1111/j.1440-1797.2006.00558.x

    Article  CAS  Google Scholar 

  13. Liu HB, Meng QH, Huang C, Wang JB, Liu XW (2015) Nephroprotective effects of polydatin against ischemia/reperfusion injury: a role for the PI3K/Akt signal pathway. Oxid Med Cell Longev 2015:362158. https://doi.org/10.1155/2015/362158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu LJ, Yu JJ, Xu XL (2018) Kappa-opioid receptor agonist U50448H protects against renal ischemia-reperfusion injury in rats via activating the PI3K/Akt signaling pathway. Acta Pharmacol Sin 39:97–106. https://doi.org/10.1038/aps.2017.51

    Article  CAS  PubMed  Google Scholar 

  15. Oba S, Suzuki E, Nishimatsu H, Kumano S, Hosoda C, Homma Y, Hirata Y (2012) Renoprotective effect of erythropoietin in ischemia/reperfusion injury: possible roles of the Akt/endothelial nitric oxide synthase-dependent pathway. Int J Urol 19:248–255. https://doi.org/10.1111/j.1442-2042.2011.02920.x

    Article  CAS  PubMed  Google Scholar 

  16. Kim SS, Shin N, Bae SS, Lee MY, Rhee H, Kim IY, Seong EY, Lee DW, Lee SB, Kwak IS, Lovett DH, Song SH (2017) Enhanced expression of two discrete isoforms of matrix metalloproteinase-2 in experimental and human diabetic nephropathy. PLoS ONE 12:e0171625. https://doi.org/10.1371/journal.pone.0171625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zheng X, Feng B, Chen G, Zhang X, Li M, Sun H, Liu W, Vladau C, Liu R, Jevnikar AM, Garcia B, Zhong R, Min WP (2006) Preventing renal ischemia-reperfusion injury using small interfering RNA by targeting complement 3 gene. Am J Transplant 6:2099–2108. https://doi.org/10.1111/j.1600-6143.2006.01427.x

    Article  CAS  PubMed  Google Scholar 

  18. Lan A, Zhang J, Xiao Z, Peng X, Qi Y, Du J (2014) Akt2 is involved in loss of epithelial cells and renal fibrosis following unilateral ureteral obstruction. PLoS ONE 9:e105451. https://doi.org/10.1371/journal.pone.0105451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kaushal GP, Basnakian AG, Shah SV (2004) Apoptotic pathways in ischemic acute renal failure. Kidney Int 66:500–506. https://doi.org/10.1111/j.1523-1755.2004.761_6.x

    Article  CAS  PubMed  Google Scholar 

  20. Han SJ, Lee HT (2019) Mechanisms and therapeutic targets of ischemic acute kidney injury. Kidney Res Clin Pract 38:427–440. https://doi.org/10.23876/j.krcp.19.062

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kwon DS, Kwon CH, Kim JH, Woo JS, Jung JS, Kim YK (2006) Signal transduction of MEK/ERK and PI3K/Akt activation by hypoxia/reoxygenation in renal epithelial cells. Eur J Cell Biol 85:1189–1199. https://doi.org/10.1016/j.ejcb.2006.06.001

    Article  CAS  PubMed  Google Scholar 

  22. Tsuruta F, Masuyama N, Gotoh Y (2002) The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J Biol Chem 277:14040–14047. https://doi.org/10.1074/jbc.M108975200

    Article  CAS  PubMed  Google Scholar 

  23. Bonventre JV, Zuk A (2004) Ischemic acute renal failure: an inflammatory disease? Kidney Int 66:480–485. https://doi.org/10.1111/j.1523-1755.2004.761_2.x

    Article  CAS  PubMed  Google Scholar 

  24. Zhang H, Sun SC (2015) NF-kappaB in inflammation and renal diseases. Cell Biosci 5:63. https://doi.org/10.1186/s13578-015-0056-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Loverre A, Ditonno P, Crovace A, Gesualdo L, Ranieri E, Pontrelli P, Stallone G, Infante B, Schena A, Di Paolo S, Capobianco C, Ursi M, Palazzo S, Battaglia M, Selvaggi FP, Schena FP, Grandaliano G (2004) Ischemia-reperfusion induces glomerular and tubular activation of proinflammatory and antiapoptotic pathways: differential modulation by rapamycin. J Am Soc Nephrol 15:2675–2686. https://doi.org/10.1097/01.ASN.0000139932.00971.E4

    Article  CAS  PubMed  Google Scholar 

  26. Madrid LV, Wang CY, Guttridge DC, Schottelius AJ, Baldwin AS Jr, Mayo MW (2000) Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol 20:1626–1638. https://doi.org/10.1128/mcb.20.5.1626-1638.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao L, Lee JY, Hwang DH (2008) The phosphatidylinositol 3-kinase/Akt pathway negatively regulates Nod2-mediated NF-kappaB pathway. Biochem Pharmacol 75:1515–1525. https://doi.org/10.1016/j.bcp.2007.12.014

    Article  CAS  PubMed  Google Scholar 

  28. Guha M, Mackman N (2002) The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277:32124–32132. https://doi.org/10.1074/jbc.M203298200

    Article  CAS  PubMed  Google Scholar 

  29. Aksoy E, Vanden Berghe W, Detienne S, Amraoui Z, Fitzgerald KA, Haegeman G, Goldman M, Willems F (2005) Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-kappa B activation and IFN-beta synthesis downstream of Toll-like receptor 3 and 4. Eur J Immunol 35:2200–2209. https://doi.org/10.1002/eji.200425801

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017R1D1A1B03034926).

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Authors and Affiliations

  1. Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea

    Il Young Kim, Sang Heon Song, Eun Young Seong, Dong Won Lee & Soo Bong Lee

  2. Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea

    Il Young Kim, Yeon Kyeong Park, Dong Won Lee & Soo Bong Lee

  3. Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea

    Sang Heon Song & Eun Young Seong

  4. MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea

    Sun Sik Bae

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  1. Il Young Kim
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Contributions

IYK, SHS, SSB, and SBL designed the study. IYK and YKP performed experiments. IYK, YKP, SHS, EYS, DWL, SSB, and SBL analyzed and interpreted data. IYK and SBL wrote the manuscript. SHS, EYS, DWL, SSB, and SBL supervised the study. All authors approved the final manuscript.

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Correspondence to Soo Bong Lee.

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The authors declare no conflicts of interest.

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Study animal protocols (PNU 2015-0909, 0998) were reviewed and approved by Pusan National University–Institutional Animal Care and Use Committee (PNU-IACUC) with respect to ethics and husbandry.

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Kim, I.Y., Park, Y.K., Song, S.H. et al. Akt1 is involved in tubular apoptosis and inflammatory response during renal ischemia–reperfusion injury. Mol Biol Rep 47, 9511–9520 (2020). https://doi.org/10.1007/s11033-020-06021-1

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