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Abstract: TH-PO103

Cancer-Derived Extracellular Vesicles Worsen Sepsis-Induced AKI

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tsuji, Takayuki, National Institutes of Health, Bethesda, Maryland, United States
  • Tsuji, Naoko, National Institutes of Health, Bethesda, Maryland, United States
  • Naito, Yoshitaka, National Institutes of Health, Bethesda, Maryland, United States
  • Hayase, Naoki, National Institutes of Health, Bethesda, Maryland, United States
  • Hu, Xuzhen, National Institutes of Health, Bethesda, Maryland, United States
  • Yuen, Peter S.T., National Institutes of Health, Bethesda, Maryland, United States
  • Star, Robert A., National Institutes of Health, Bethesda, Maryland, United States
Background

Patients with hematological malignancies are at high risk for acute kidney injury (AKI). We established a mouse xenograft model of acute myeloid leukemia (AML)-associated sepsis AKI. We found that AML worsened sepsis AKI (ASN 2020). However, it is not known what leukemia-associated factors contribute to the deterioration of AKI. It has been reported that cancer-derived extracellular vesicles (EVs) have various effects on host immune cells and hematopoiesis. We hypothesized that AML cell-derived EVs worsen sepsis AKI.

Methods

AML cells (Human Leukemia HL60 cells) were incubated in serum free medium for 48 h to obtain AML cell-derived EVs. Large and small EVs were isolated by a differential centrifugation procedure (14K x g and 200K x g) and quantitated by Zetaview. To examine the effect of EVs on sepsis-induced AKI, cecal ligation and puncture (CLP) was performed to induce sepsis in male CD-1 mice (n=8-10 per group), and EVs or PBS were injected intravenously at the time of CLP surgery. Multiple organ damage, splenic apoptosis and mouse systemic cytokines were evaluated at 24 h after CLP or sham surgery.

Results

EVs obtained from 14K x g pellet (EVs(14K)) intensified sepsis-induced organ damage including AKI. BUN, LDH, AST and ALT were significantly higher in EVs(14K)+CLP than both EVs(200K)+CLP and PBS+CLP (EVs(14K)+CLP, EVs(200K)+CLP, PBS+CLP. BUN; 127.0±13.8, 59.4±33.3, 67.0±43.6 mg/dl, LDH; 4,007±1,378, 2,221±1,040, 3,111±714 U/l, AST; 817±268, 487±147, 514±137 U/l p<0.05). Kidney histological damage and splenic apoptosis were significantly worse in EVs(14K)+CLP compared to either EVs(200K)+CLP or PBS+CLP. Systemic cytokines at 24 h after CLP were significantly higher in EVs(14K)+CLP than either EVs(200K)+CLP or PBS+CLP (TNFα; 628±220, 149±107, 281±195 pg/ml, IL-6; 119±61, 41±29, 56±59 ng/ml, IL-10; 4,810±1,494, 1,470±913, 2,607±805 pg/ml, p<0.05).

Conclusion

We found that AML cell-derived EVs obtained from 14K x g pellet, but not 200K x g pellet worsened sepsis AKI. Therefore, the impact of leukemia can be largely recapitulated by administration of EVs. Further study is needed to determine what components within EVs are responsible for this worsening of sepsis AKI. Additionally, mechanistic insights may inform how to therapeutically target these EVs during septic episodes in leukemia patients.

Funding

  • NIDDK Support