Abstract: FR-PO947
Amphiregulin Mediated Cellular Reprogramming Modulates Inflammation and Tissue Remodeling Following Kidney Injury
Session Information
- Development, Stem Cells, Regenerative Medicine - II
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Development, Stem Cells, and Regenerative Medicine
- 501 Development, Stem Cells, and Regenerative Medicine: Basic
Authors
- Sabapathy, Vikram, University of Virginia, Charlottesville, Virginia, United States
- Cheru, Nardos Tesfaye, University of Virginia, Charlottesville, Virginia, United States
- Mohammad, Saleh, University of Virginia, Charlottesville, Virginia, United States
- Venkatadri, Rajkumar, University of Virginia, Charlottesville, Virginia, United States
- Sharma, Rahul, University of Virginia, Charlottesville, Virginia, United States
Background
Acute Kidney injury (AKI) is a major cause of mortality and morbidity. There is a growing evidence of interaction between tissue-resident immune cells and epithelial progenitor cells that participate in the process of regeneration. Recent studies indicate that Amphiregulin (AREG), a member of epidermal growth factor (EGF) family, also secreted by immune cells and has been shown to modulate both host immunity and tolerance mechanism. We hypothesize that AREG, produced by Regulatory T Cells (Tregs) promotes tissue repair and regeneration. In this study, we investigated differential effects of AREG towards promoting tissue homeostasis and regeneration using both in vivo and in vitro models.
Methods
Murine ischemia-reperfusion injury (IRI) and Endotoxemic renal injury models were developed to investigate a therapeutic effect of AREG. The protective effect of cytokine treatment both before and after the injury was examined. The structure and function of the kidney were probed using flow cytometry, intravital microscopy, histology, immunohistochemistry, quantitative gene expression and biochemical analysis. Kidney organoids and tubular epithelial cell line were used to probe the efficacy of AREG under in vitro conditions.
Results
Our findings showed that treatment with AREG immediately after injury not only enhanced the expansion of Tregs but also accentuates the suppressive function of Tregs, thus preventing kidney damage and preserving renal function in murine models. On the other hand, impediment of EGFR signaling resulted in increased fibrosis and deterioration of kidney function. Experiments using kidney organoids showed that addition of exogenous AREG attenuated cell death in an in vitro model of injury. Interestingly, direct addition of AREG to proximal tubular epithelial cell culture resulted in the development of cellular plasticity. Furthermore, AREG knockout mouse model was used to elucidate the role of AREG mediated regeneration in AKI.
Conclusion
This study addresses the application of AREG in immunomodulation and renal regeneration as a therapeutic approach for renal injury and sheds light on the mechanisms enforced by immune cells in the switch of maladaptive repair to successful regeneration.
Funding
- NIDDK Support – AstraZeneca-UVA Alliance for Diabetic Nephropathy (RS)