Abstract: FR-PO109
Sepsis Alters Renal Tubular Epithelial Phenotype and Disrupts Intercellular Communication
Session Information
- AKI: Mechanisms - Inflammation/Sepsis/Remote Injury
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Janosevic, Danielle, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Myslinski, Jered, Indiana University School of Medicine, Indianapolis, Indiana, United States
- McCarthy, Thomas Wayne, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Hato, Takashi, Indiana University, Indianapolis, Indiana, United States
- Dagher, Pierre C., Indiana University, Indianapolis, Indiana, United States
Background
The success of sepsis therapy requires an understanding of time and cell-specific responses to infection. Such knowledge will allow accurate staging of septic patients and precise spatial and temporal therapy. We recently showed that the renal response to endotoxin (LPS) involves the sequential activation of inflammation, antiviral signaling and translation shutdown leading to organ failure. This propagation of injury was mediated in part by tubular epithelial and macrophage cross-talk. However, the kidney is composed of over twenty cell populations including epithelial, endothelial, immune and stromal cells. We therefore hypothesize that many of these cell types have precise roles in injury propagation along the sepsis timeline. To address this hypothesis, we used single cell RNAseq to dissect each cell subpopulation’s contribution to endotoxin injury over time.
Methods
We harvested single cell suspensions from murine kidneys at time points spanning the injury and recovery phases of sepsis. Cells were processed via 10x Chromium RNA sequencing platform and analyzed with Seurat R package.
Results
We identified 26 clusters representative of major renal cell populations defined by known canonical markers. Endothelial cells and macrophages showed early transcriptional changes but opposite metabolic profiles. Interestingly, the pericyte also showed early signaling activation that persisted well into the recovery phase. In contrast, tubular epithelia exhibited a delayed response characterized by loss of expression of traditional markers such as the tubular SGLT2 transporter while simultaneously acquiring novel phenotypes such as the unexpected expression of antigen presenting MHC-II-related genes. This may indicate that under stress, epithelial cells assume the role of defenders rather than transporters. Remarkably, CellPhone Database analysis identified global shutdown of intercellular communication in the absence of cell death.
Conclusion
We propose that, in addition to propagation of injurious signaling, organ shutdown in sepsis also results from failure of cell-cell communication. This time-layered, cell-specific approach to the pathophysiology of sepsis may reveal biomarkers that allow the accurate staging of septic patients and identify temporally and spatially precise therapeutic targets.
Funding
- Other NIH Support