Volume 13 Issue 6
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Zhu Jiefu, Shi Lang, Song Zhixia, et al. Role and mechanism of GDF15 in ischemia-reperfusion injury during kidney transplantation[J]. ORGAN TRANSPLANTATION, 2022, 13(6): 749-756. doi: 10.3969/j.issn.1674-7445.2022.06.009
Citation: Zhu Jiefu, Shi Lang, Song Zhixia, et al. Role and mechanism of GDF15 in ischemia-reperfusion injury during kidney transplantation[J]. ORGAN TRANSPLANTATION, 2022, 13(6): 749-756. doi: 10.3969/j.issn.1674-7445.2022.06.009
shu

Role and mechanism of GDF15 in ischemia-reperfusion injury during kidney transplantation

doi: 10.3969/j.issn.1674-7445.2022.06.009

  • Department of Organ Transplantation, People's Hospital of Wuhan University, Wuhan 430060, China

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  • Corresponding author: Wu Xiongfei, Email: wuxfei@126.com
  • Received Date: 2022-08-31
    Available Online: 2022-11-14
  • Publish Date: 2022-11-15
    Abstract
  •   Objective  To investigate the role and mechanism of growth differentiation factor (GDF) 15 in ischemia-reperfusion injury (IRI) during kidney transplantation.  Methods  Nine wild type donor mice and 9 wild type recipient mice were selected. The renal graft of 3 recipient mice were harvested at 4, 24 and 72 h after transplantation. GDF family transcriptome analysis was carried out, and the expression of GDF15 in renal tissues of each group were detected. Five wild type donor mice, 5 GDF15 knockout donor mice and 10 wild type recipient mice were selected. According to the experimental scheme, the mice were divided into wild type sham operation group, wild type transplantation group, GDF15 knockout sham operation group and GDF15 knockout transplantation group. Serum and renal tissue samples were extracted 72 h after transplantation. The renal function, renal tubular injury, inflammatory cell infiltration, inflammatory factors, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB expression level were compared in each group. Nine wild type donor mice, 9 GDF15 knockout donor mice and 18 wild type recipient mice were selected. According to the experimental scheme, the mice were divided into wild type transplantation group and GDF15 knockout transplantation group, and the survival rate of two group after kidney transplantation was observed.  Results  Transcriptome sequencing of renal graft tissues indicated that GDF15 was the most up-regulated GDF family gene, which was mainly expressed in renal tubules. Compared with the sham operation group, the renal function of mice was declined in the transplantation group. Compared with the wild type transplantation group, the serum creatinine and blood urea nitrogen levels of mice were significantly up-regulated in the GDF15-knockout transplantation group (both P < 0.05). The 1-week survival rate of mice was 87.6% in the wild type transplantation group and 41.8% in the GDF15 knockout transplantation group. In the GDF15 knockout transplantation group, the expression level of kidney injury molecule (KIM)-1 was up-regulated, and the renal tubule injury score was increased. In the wild type transplantation group, the renal tubules were dissolved or necrotized, and tubular formation was seen in the extramedullary and cortex area, whereas tubular necrosis and tubular formation were more evident in the GDF15 knockout transplantation group. The expression levels of myeloperoxidase (MPO) and F4/80 were up-regulated in the transplantation group, and the inflammatory cell infiltration was aggravated in the GDF15 knockout transplantation group. Compared with the sham operation group, the expression levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the transplantation group were up-regulated. Compared with the wild type transplantation group, the expression levels of TNF-α, IL-1β and IL-6 were also up-regulated in the GDF15 knockout transplantation group (all P < 0.05). In the transplantation group, the expression levels of TLR4 and NF-κB in the renal graft tissues were higher than those in the sham operation group. In the GDF15 knockout transplantation group, the expression levels of TLR4 and NF-κB in the renal graft tissues were higher compared with those in the wild type transplantation group.  Conclusions  GDF15 may alleviate the IRI of renal graft probably via inhibiting the TLR4-NF-κB signaling pathway.

     

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    • References(30)
  • [1]
    HART A, LENTINE KL, SMITH JM, et al. OPTN/SRTR 2019 annual data report: kidney[J]. Am J Transplant, 2021, 21(Suppl 2): 21-137. DOI: 10.1111/ajt.16502.
    [2]
    MUDIAYI D, SHOJAI S, OKPECHI I, et al. Global estimates of capacity for kidney transplantation in world countries and regions[J]. Transplantation, 2022, 106(6): 1113-1122. DOI: 10.1097/TP.0000000000003943.
    [3]
    李峰, 浦金贤, 黄玉华, 等. 肾损伤标志物对肾移植受者发生DGF的早期预测价值[J]. 器官移植, 2022, 13(1): 74-79. DOI: 10.3969/j.issn.1674-7445.2022.01.012.

    LI F, PU JX, HUANG YH, et al. Predictive value of kidney injury markers for early DGF in kidney transplant recipients[J]. Organ Transplant, 2022, 13(1): 74-79. DOI: 10.3969/j.issn.1674-7445.2022.01.012.
    [4]
    TULLIUS SG, RABB H. Improving the supply and quality of deceased-donor organs for transplantation[J]. N Engl J Med, 2018, 379(7): 693-694. DOI: 10.1056/NEJMc1808003.
    [5]
    SCHRÖPPEL B, LEGENDRE C. Delayed kidney graft function: from mechanism to translation[J]. Kidney Int, 2014, 86(2): 251-258. DOI: 10.1038/ki.2014.18.
    [6]
    WANG D, DAY EA, TOWNSEND LK, et al. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease[J]. Nat Rev Endocrinol, 2021, 17(10): 592-607. DOI: 10.1038/s41574-021-00529-7.
    [7]
    UNSICKER K, SPITTAU B, KRIEGLSTEIN K. The multiple facets of the TGF-β family cytokine growth/differentiation factor-15/macrophage inhibitory cytokine-1[J]. Cytokine Growth Factor Rev, 2013, 24(4): 373-384. DOI: 10.1016/j.cytogfr.2013.05.003.
    [8]
    CHEN W, TEN DIJKE P. Immunoregulation by members of the TGFβ superfamily[J]. Nat Rev Immunol, 2016, 16(12): 723-740. DOI: 10.1038/nri.2016.112.
    [9]
    MULDERRIG L, GARAYCOECHEA JI, TUONG ZK, et al. Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response[J]. Nature, 2021, 600(7887): 158-163. DOI: 10.1038/s41586-021-04133-7.
    [10]
    NAKAYASU ES, SYED F, TERSEY SA, et al. Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention[J]. Cell Metab, 2020, 31(2): 363-374. DOI: 10.1016/j.cmet.2019.12.005.
    [11]
    COLL AP, CHEN M, TASKAR P, et al. GDF15 mediates the effects of metformin on body weight and energy balance[J]. Nature, 2020, 578(7795): 444-448. DOI: 10.1038/s41586-019-1911-y.
    [12]
    BORNER T, SHAULSON ED, GHIDEWON MY, et al. GDF15 induces anorexia through nausea and emesis[J]. Cell Metab, 2020, 31(2): 351-362. DOI: 10.1016/j.cmet.2019.12.004.
    [13]
    SUN L, ZHOU X, JIANG J, et al. Growth differentiation factor-15 levels and the risk of contrast induced nephropathy in patients with acute myocardial infarction undergoing percutaneous coronary intervention: a retrospective observation study[J]. PLoS One, 2018, 13(5): e0197609. DOI: 10.1371/journal.pone.0197609.
    [14]
    KAHLI A, GUENANCIA C, ZELLER M, et al. Growth differentiation factor-15 (GDF-15) levels are associated with cardiac and renal injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass[J]. PLoS One, 2014, 9(8): e105759. DOI: 10.1371/journal.pone.0105759.
    [15]
    GUENANCIA C, KAHLI A, LAURENT G, et al. Pre-operative growth differentiation factor 15 as a novel biomarker of acute kidney injury after cardiac bypass surgery[J]. Int J Cardiol, 2015, 197: 66-71. DOI: 10.1016/j.ijcard.2015.06.012.
    [16]
    SUN L, ZHOU X, JIANG J, et al. Growth differentiation factor-15 levels and the risk of contrast induced acute kidney injury in acute myocardial infarction patients treated invasively: a propensity-score match analysis[J]. PLoS One, 2018, 13(3): e0194152. DOI: 10.1371/journal.pone.0194152.
    [17]
    DE COS GOMEZ M, GARCIA UNZUETA MT, BENITO HERNANDEZ A, et al. Growth differentiation factor 15 is superior to troponin I in the evaluation of kidney transplant candidates[J]. Am J Nephrol, 2022, 53(2/3): 118-128. DOI: 10.1159/000521781.
    [18]
    LUAN HH, WANG A, HILLIARD BK, et al. GDF15 is an inflammation-induced central mediator of tissue tolerance[J]. Cell, 2019, 178(5): 1231-1244. DOI: 10.1016/j.cell.2019.07.033.
    [19]
    PATSALOS A, HALASZ L, MEDINA-SERPAS MA, et al. A growth factor-expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15[J]. J Exp Med, 2022, 219(1): e20210420. DOI: 10.1084/jem.20210420.
    [20]
    ZHU J, ZHANG G, SONG Z, et al. Protein kinase C-δ mediates kidney tubular injury in cold storage-associated kidney transplantation[J]. J Am Soc Nephrol, 2020, 31(5): 1050-1065. DOI: 10.1681/ASN.2019101060.
    [21]
    HART A, SMITH JM, SKEANS MA, et al. OPTN/SRTR 2017 annual data report: kidney[J]. Am J Transplant, 2019, 19(Suppl 2): 19-123. DOI: 10.1111/ajt.15274.
    [22]
    TUEGEL C, KATZ R, ALAM M, et al. GDF-15, galectin 3, soluble ST2, and risk of mortality and cardiovascular events in CKD[J]. Am J Kidney Dis, 2018, 72(4): 519-528. DOI: 10.1053/j.ajkd.2018.03.025.
    [23]
    WU H, CHEN G, WYBURN KR, et al. TLR4 activation mediates kidney ischemia/reperfusion injury[J]. J Clin Invest, 2007, 117(10): 2847-2859. DOI: 10.1172/JCI31008.
    [24]
    VALIÑO-RIVAS L, CUARENTAL L, CEBALLOS MI, et al. Growth differentiation factor-15 preserves Klotho expression in acute kidney injury and kidney fibrosis[J]. Kidney Int, 2022, 101(6): 1200-1215. DOI: 10.1016/j.kint.2022.02.028.
    [25]
    PEREZ-GOMEZ MV, PIZARRO-SANCHEZ S, GRACIA-IGUACEL C, et al. Urinary growth differentiation factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease[J]. J Nephrol, 2021, 34(6): 1819-1832. DOI: 10.1007/s40620-021-01020-2.
    [26]
    LAUCYTE-CIBULSKIENE A, WARD LJ, EBERT T, et al. Role of GDF-15, YKL-40 and MMP 9 in patients with end-stage kidney disease: focus on sex-specific associations with vascular outcomes and all-cause mortality[J]. Biol Sex Differ, 2021, 12(1): 50. DOI: 10.1186/s13293-021-00393-0.
    [27]
    CIESIELSKA A, MATYJEK M, KWIATKOWSKA K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling[J]. Cell Mol Life Sci, 2021, 78(4): 1233-1261. DOI: 10.1007/s00018-020-03656-y.
    [28]
    JAIN S, PLENTER R, NYDAM T, et al. Deletion of TLR4 reduces apoptosis and improves histology in a murine kidney transplant model[J]. Sci Rep, 2021, 11(1): 16182. DOI: 10.1038/s41598-021-95504-7.
    [29]
    CONTE M, GIULIANI C, CHIARIELLO A, et al. GDF15, an emerging key player in human aging[J]. Ageing Res Rev, 2022, 75: 101569. DOI: 10.1016/j.arr.2022.101569.
    [30]
    KEIPERT S, OST M. Stress-induced FGF21 and GDF15 in obesity and obesity resistance[J]. Trends Endocrinol Metab, 2021, 32(11): 904-915. DOI: 10.1016/j.tem.2021.08.008.
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