Abstract: PO2476
Spiny Mice (Acomys cahirinus) Activate Unique Transcriptional Programs After Severe Kidney Injuries and Regenerate Organ Function Without Fibrosis
Session Information
- CKD: Inflammation, Endothelial Dysfunction, and Signaling
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Okamura, Daryl M., Seattle Children's Research Institute, Seattle, Washington, United States
- Brewer, Chris M., Seattle Children's Research Institute, Seattle, Washington, United States
- Collins, Sarah J., Seattle Children's Research Institute, Seattle, Washington, United States
- Nguyen, Elizabeth D., Seattle Children's Research Institute, Seattle, Washington, United States
- Piliponsky, Adrian, Seattle Children's Research Institute, Seattle, Washington, United States
- Nelson, Branden R., Seattle Children's Research Institute, Seattle, Washington, United States
- Beier, David R., Seattle Children's Research Institute, Seattle, Washington, United States
- Millen, Kathleen J., Seattle Children's Research Institute, Seattle, Washington, United States
- Majesky, Mark W., Seattle Children's Research Institute, Seattle, Washington, United States
Background
Fibrosis-driven solid organ failure is a pervasive burden on global health. Muroid rodents of the genus Acomys (spiny mice) are terrestrial mammals that evolved remarkable abilities to regenerate severe skin wounds without scar formation to avoid predation. Whether regenerative wound healing extends beyond skin to vital internal organs in spiny mice is not known.
Methods
Models of acute and chronic kidney injury (UUO, unilateral IRI, unilateral IRI+nephrectomy) were utilized in Acomys and compared to C57Bl6/J and CD-1 mice. Fibrosis, myofibroblasts, macrophages were measured. Total kidney RNA Seq, western blotting and confocal image analysis was performed.
Results
Using two aggressive kidney injury models, we show that despite equivalent kidney injury there was rapid regeneration of nephron structure and function without fibrosis in Acomys compared to extensive fibrosis and renal failure in Mus. Comparative genome-wide analysis of gene expression after injury suggested that the Acomys genome is poised to initiate and sustain regenerative wound healing. Among the 843 differentially regulated genes between Acomys and Mus were metabolic enzymes, transcription factors, and nephrogenic genes such as Osr1, Ror1/2 and Cdh6. Interaction analyses revealed 6 clusters of genes that were differentially regulated with injury between Mus and Acomys. Clusters 1 and 4 represented Mus-specific genomic responses to UUO injury whereas the response to injury in Acomys is to maintain expression at homeostatic levels. In contrast, clusters 2 and 3 represent Acomys-specific kidney response gene sets which are unchanged or downregulated in Mus. Early after injury, a cluster 3 gene, Cdh6 appeared in rapidly expanding renal tubular mosaic patches throughout the injured Acomys, but not Mus. Regeneration of nephron function was accompanied by cell cycle entry and DNA replication in tubular and glomerular cells, including podocytes and endothelial cells.
Conclusion
Our findings have important implications for an evolutionary solution to mammalian regenerative repair of the kidney, and by extension, to the heart and coronary vessels, lungs, liver, and other internal organs similarly prone to organ failure as a result of progressive tissue fibrosis.
Funding
- NIDDK Support