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Abstract: SA-PO105

Discovery of Osteopontin-Dependent and Independent Signaling Networks in AKI-Induced Remote Acute Lung Injury (AKI-ALI)

Session Information

  • AKI: Mechanisms - III
    November 05, 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

  • Komaru, Yohei, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • Ning, Liang, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • Kefalogianni, Eirini, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • Herrlich, Andreas, Washington University in St Louis School of Medicine, St Louis, Missouri, United States

Group or Team Name

  • Division of Nephrology
Background

Using scRNAseq and ligand-receptor pairing analysis across organs, we identified circulating osteopontin (OPN) released from the AKI kidney and deposited into the lung as a causal agent of AKI-ALI [Khamissi et al. Science Advances 2022]. Direct ALI complicated by AKI is a frequent clinical problem with high mortality. How AKI modifies ALI outcomes and whether AKI-released OPN deposited into the lung acts as a negative modifier of direct ALI is unknown.

Methods

Single-cell RNA sequencing (scRNAseq) of lung or kidney after sham or AKI (ischemia reperfusion injury). Interorgan cell communications were identified using scRNAseq analysis with CellPhone DB or CellChat. Direct ALI was induced with intratracheally instilled lipopolysaccharide (LPS-ALI). In a two-hit model, renal IRI was added 24 hours after LPS-ALI.

Results

OPN injection is not sufficient to induce ALI in uninjured mice, thus additional AKI-released mediators are involved. We initially focused on OPN-dependent kidney-lung networks, which were increased by 3-fold in AKI as compared to the sham. In AKI, the average interaction strength was increased by 90%. Baseline OPN signals towards lung immune cells mainly originated from the proximal and distal tubules. These OPN-dependent signals likely represent early AKI-ALI mediators that don't require transcriptional upregulation. Analysis of OPN-independent kidney to lung networks revealed that total kidney-lung connections were very similar in number and strength between sham and AKI. However, several signaling networks significantly differed in AKI vs sham, likely indicating novel relevant signals for AKI-ALI emanating from the kidney.
We hypothesized further that AKI-released osteopontin could modify pre-existing ALI outcomes. We found that OPN protein expression in the directly LPS-injured lung was moderately elevated. However, addition of AKI after direct LPS-induced ALI further significantly increased OPN protein accumulation in the lung. This suggests a mechanistic connection between kidney-released and lung deposited OPN and the clinically observed worsening of direct ALI outcomes in the context of AKI.

Conclusion

Studies integrating single-cell transcriptomics and in vivo models enable elucidation of novel mechanism(s) of AKI-ALI in clinically relevant contexts at the cell-type and signal-pathway level.

Funding

  • NIDDK Support