Exosome-based delivery of super-repressor IκBα ameliorates kidney ischemia-reperfusion injury

Seonghun Kim, Sul A. Lee, Heakyung Yoon, Myung Yoon Kim, Jae Kwang Yoo, So Hee Ahn, Cheol Hyoung Park, Jimin Park, Bo Young Nam, Jung Tak Park, Seung Hyeok Han, Shin Wook Kang, Nam Hee Kim, Hyun Sil Kim, Dawool Han, Jong In Yook, Chulhee Choi, Tae Hyun Yoo

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

Ischemia-reperfusion injury is a major cause of acute kidney injury. Recent studies on the pathophysiology of ischemia-reperfusion-induced acute kidney injury showed that immunologic responses significantly affect kidney ischemia-reperfusion injury and repair. Nuclear factor (NF)-ĸB signaling, which controls cytokine production and cell survival, is significantly involved in ischemia-reperfusion-induced acute kidney injury, and its inhibition can ameliorate ischemic acute kidney injury. Using EXPLOR, a novel, optogenetically engineered exosome technology, we successfully delivered the exosomal super-repressor inhibitor of NF-ĸB (Exo-srIĸB) into B6 wild type mice before/after kidney ischemia-reperfusion surgery, and compared outcomes with those of a control exosome (Exo-Naïve)-injected group. Exo-srIĸB treatment resulted in lower levels of serum blood urea nitrogen, creatinine, and neutrophil gelatinase-associated lipocalin in post-ischemic mice than in the Exo-Naïve treatment group. Systemic delivery of Exo-srIĸB decreased NF-ĸB activity in post-ischemic kidneys and reduced apoptosis. Post-ischemic kidneys showed decreased gene expression of pro-inflammatory cytokines and adhesion molecules with Exo-srIĸB treatment as compared with the control. Intravital imaging confirmed the uptake of exosomes in neutrophils and macrophages. Exo-srIĸB treatment also significantly affected post-ischemic kidney immune cell populations, lowering neutrophil, monocyte/macrophage, and T cell frequencies than those in the control. Thus, modulation of NF-ĸB signaling through exosomal delivery can be used as a novel therapeutic method for ischemia-reperfusion-induced acute kidney injury.

Original languageEnglish
Pages (from-to)570-584
Number of pages15
JournalKidney International
Volume100
Issue number3
DOIs
Publication statusPublished - 2021 Sep

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF-2017R1A2B4005720, NRF-2017R1A2B3002241, NRF-2018M3A9E2022820, NRF-2019R1A2C2084535, NRF-2020R1I1A1A01072977), which is funded by the Korean government (MSIP and MOE). This study was also supported by ILIAS Biologics Inc. based on the Sponsored Research Agreement (SRA) between MET Inc. and ILIAS Biologics Inc. and Yonsei University College of Medicine and ILIAS Biologics Inc. The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine, for all artistic support related to this work. SK and T-HY conceived and designed the project, and JIY, CC, and T-HY supervised and developed the study. SK, SAL, HY, MYK, J-KY, S-HA, NHK, and HSK conducted experiments. SK and SAL acquired data. SK, JP, BYN, and JIY analyzed data, and SK and SAL wrote the manuscript. T-HY, CHP, J-KY, JTP, SHH, and S-WK reviewed the manuscript and provided suggestions for further development.

Funding Information:
This work was supported by grants from the National Research Foundation of Korea (NRF-2017R1A2B4005720, NRF-2017R1A2B3002241, NRF-2018M3A9E2022820, NRF-2019R1A2C2084535, NRF-2020R1I1A1A01072977), which is funded by the Korean government (MSIP and MOE). This study was also supported by ILIAS Biologics Inc., based on the Sponsored Research Agreement (SRA) between MET Inc. and ILIAS Biologics Inc., and Yonsei University College of Medicine and ILIAS Biologics Inc. The authors thank Medical Illustration & Design, part of the Medical Research Support Services of Yonsei University College of Medicine , for all artistic support related to this work.

Publisher Copyright:
© 2021 International Society of Nephrology

All Science Journal Classification (ASJC) codes

  • Nephrology

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