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Abstract: SA-PO184

Integrin β1-Rich Extracellular Vesicles of Kidney Tissue Recruit Fn1+ Macrophages to Aggravate Ischaemia-Reperfusion-Induced Inflammation

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wang, Wenjuan, Nankai University School of Medicine, Tianjin, Tianjin, China
  • Hong, Quan, First Medical Center of Chinese PLA General Hospital Nephrology Institute of the Chinese People's Liberation Army, Beijing, Beijing, China
  • Cai, Guangyan, First Medical Center of Chinese PLA General Hospital Nephrology Institute of the Chinese People's Liberation Army, Beijing, Beijing, China
Background

Ischaemia-reperfusion injury (IRI)-induced acute kidney injury is accompanied by mononuclear phagocyte/macrophagocyte (MP) invasion and inflammation. However, the exact kidney-derived extracellular vesicle (EV)-carried proteins that mediate intercellular crosstalk remain elusive.

Methods

Multiomics analysis combining scRNA-seq data and kidney EV protein profiling was used to explore the transcriptomic diversity of proximal tubular cells (PTs) and MPs and differential protein expression of kidney EVs to elucidate how the PT-MP interaction amplifies local inflammation. Transmission electron microscopy, nanoparticle tracking analysis, co-immunoprecipitation, molecular docking, co-culture experiments, siRNA transfection technology, flow cytometry, RT-qPCR, western blotting, and immunohistochemistry were used for verification of functional experiments.

Results

Targeted adhesion and migration of various MPs were caused by secretion of multiple chemokines as well as the integrin β1-rich EVs by ischemic damaged PTs after IRI. These recruited MPs, especially Fn1+ Macs, amplified the surviving PTs’ inflammatory response by secreting inflammatory factor TNF-α, Ccl2, and thrombospondin 1 (THBS-1), which could interact with integrin β1 to promote more MP adhesion as well as interact with CD36 to further promote the secretion of IL-1β from surviving PTs. However, blocking EVs with GW4869 maintained a moderate inflammatory response by reducing MP infiltration, promoting repair.

Conclusion

Our findings establish the molecular bases by which chemokines and kidney EVs mediate PT-MP crosstalk in early IRI and provide new insights into systematic intercellular communication.

Summary of renal inflammation especially mediated by the intercellular crosstalk among PTs and MPs following IRI-AKI.

Funding

  • Government Support – Non-U.S.