Kidney Week

Abstract: PO0252

Single-Cell Profiling of AKI in Mice Highlights Differential Immune Cellular Response Programs in Regeneration and Fibrosis

Session Information

• AKI Mechanisms - 3
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Balzer, Michael S., University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Renal, Electrolyte and Hypertension Division, Philadelphia, Pennsylvania, United States

Michael S. Balzer,

• Yang, Yawen, University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Renal, Electrolyte and Hypertension Division, Philadelphia, Pennsylvania, United States

Yawen Yang,

• Ma, Ziyuan, University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Renal, Electrolyte and Hypertension Division, Philadelphia, Pennsylvania, United States

Ziyuan Ma,

• Shrestha, Rojesh, University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Renal, Electrolyte and Hypertension Division, Philadelphia, Pennsylvania, United States

Rojesh Shrestha,

• Palmer, Matthew, University of Pennsylvania, Perelman School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, Pennsylvania, United States

Matthew Palmer,

• Susztak, Katalin, University of Pennsylvania, Perelman School of Medicine, Department of Medicine, Renal, Electrolyte and Hypertension Division, Philadelphia, Pennsylvania, United States

Katalin Susztak,

Group or Team Name

• Susztak Lab

Background

After acute injury the kidney has the ability to regenerate and repair to a certain extent. On the other hand, maladaptive injury response leads to kidney fibrosis and chronic kidney disease. We are only beginning to understand the complex interactions of epithelial, stromal and immune cells involved in these adaptive processes.

Methods

Here we profiled gene expression changes at single cell resolution over time in acutely injured kidneys of mice subjected to mild and severe bilateral ischemic reperfusion injury (IRI). Kidney function, structure, bulk and single cell gene expression analysis was performed on day 1, 3 and 14. We used gene regulatory network and trajectory analyses to define key drivers of successful and failed regeneration.

Results

Bilateral ischemia resulted in similar kidney function decline as analyzed by serum BUN, however long ischemia led to severe kidney fibrosis, while mild ischemia prompted minimal structural changes. In total, we obtained scRNAseq data for >160,000 cells. IRI lead to very significant cell proportion changes including a decrease in renal tubule cells and increase in immune cell fractions. Proximal tubules showed distinctly different differentiation signatures for successful repair vs. maladaptive response in animals subjected to moderate vs. severe IRI. We also identified several discrete immune cell clusters, such as progenitors, naïve B and T cells, T memory and Tgd cells, natural killer and dendritic cells, Ly6Chi and lo monocytes, macrophages and granulocytes and we define their differentially expressed gene network along pseudotime trajectories towards either successful or maladaptive repair.

Conclusion

Single cell RNA-seq analysis of kidney cells revealed differential gene expression changes during regenerative vs. maladaptive response after acute injury. We define patterns of maladaptive proximal tubule repair and characterize important signatures in immune cell composition and activation in regenerating vs. fibrosing kidneys.

Funding

• NIDDK Support