Abstract: SA-PO081
Removal of Apoptotic Cells During AKI
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 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
- Morioka, Sho, University of Virginia, Charlottesville, Virginia, United States
- Tanaka, Shinji, University of Virginia, Charlottesville, Virginia, United States
- Skrypnyk, Nataliya, University of Virginia, Charlottesville, Virginia, United States
- Okusa, Mark D., University of Virginia, Charlottesville, Virginia, United States
- Ravichandran, Kodi S., University of Virginia, Charlottesville, Virginia, United States
Background
The incidence of acute kidney injury (AKI) is increasing worldwide, however, effective treatment for AKI remains elusive and no approved pharmacological agents exist. Tubular cell apoptosis has been shown to be present in preclinical models and also in some clinical samples from patients with AKI. The human body removes over 200 billion dead cells every day. This process, i.e. clearance of apoptotic cells or ‘efferocytosis’, occurs in nearly every major organ (Morioka et al., Nature 2018). Clearance machinery can often become overwhelmed by massive induction of apoptosis such as occurs with ischemia reperfusion injury (IRI). While it has been shown that defective clearance leads to exacerbation of AKI, whether promoting efferocytosis leads to amelioration of AKI has not been explored.
Methods
In order to delinate whether apoptotic cell clearance could be boosted for beneficial effects during AKI, we established a way to boost apoptotic cell clearance by modulating the protein structure of a previously characterized phosphatidylserine (PtdSer) receptor, BAI1. Previous studies have shown that while BAI1 interacts PtdSer via its extracellular region, BAI1 also binds via its cytoplasmic tail to ELMO1 and in turn, a second protein Dock180, which together serve as a guanine nucleotide exchange factor complex for the GTPase Rac1. Activation of Rac1 induces a conformational change of the actin filament to initiate the uptake of target cells. We generated a chimeric version of BAI1 where we deleted the natural ELMO1 binding site and directly fused ELMO1 to the BAI1 cytoplasmic tail (denoted BELMO).
Results
Strikingly, we found that expression of this chimeric BELMO receptor strongly boosted apoptotic cell engulfment. This chimeric receptor still behaved faithfully as it was dependent on PtdSer recognition, and an intact ELMO1 that can engage the downstream Dock180 and Rac1 signaling machinery. We have also generated transgenic mouse expressing BELMO receptor. We demonstrate that BELMO expression in tubular epithelial cells significantly improved the survival rate of the mice underwent AKI induced by renal IRI surgery.
Conclusion
Here we open up new avenue for targeting cell clearance in AKI therapy. In addition, BELMO transgenic mice allow us to explore the effect of boosting apoptotic cell clearance on variety of other disease models involving accumulation of dead cells.