Abstract: FR-PO094
Recognition of Apoptotic Cells by Viable Proximal Tubular Epithelial Cells (PTEC) Induces Death Receptor (DR)-Dependent Death of PTEC, but in a Ligand-Independent Manner
Session Information
- AKI: Tubules, Metabolism, New Models
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Dietrich, Michael E., University of Illinois at Chicago College of Medicine, Chicago, Illinois, United States
- Levine, Jerrold S., University of Illinois at Chicago College of Medicine, Chicago, Illinois, United States
- Rauch, Joyce, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Feng, Lanfei, University of Illinois at Chicago College of Medicine, Chicago, Illinois, United States
Background
We have shown that mouse kidney PTEC have distinct non-competing receptors for apoptotic and necrotic targets. Receptor-mediated recognition of apoptotic, but not necrotic, targets induces apoptotic death of PTEC responders.
Methods
Responder cells were BU.MPT cells, a conditionally immortalized PTEC line. Target cells, induced to undergo apoptosis or necrosis, were homologous (BU.MPT) or heterologous (DO11.10 lymphocytes) cells.
Results
Apoptotic target-induced death of PTEC responders is profound (~100% by 48-72 h). Target-induced apoptotic death appears to involve death receptors (DRs), as supported by the following data. First, death is associated with signaling events typical of DR-mediated apoptosis in type II epithelial cells, including cleavage of caspase-8, cleavage of the pro-apoptotic Bcl-2 family member BID to tBID, and activation of caspase-3. Second, PTEC constitutively express the DRs DR5, Fas, and TNFRI, as assessed by flow cytometry, and DR expression is significantly decreased following exposure to apoptotic targets, consistent with receptor activation and internalization. A fourth DR, DR3, is not expressed constitutively by PTEC, but is induced following exposure to apoptotic targets. Third, decreased DR expression correlates with activation of caspase-3 and induction of apoptosis. Surprisingly, DR activation appears to occur in a ligand-independent manner. No DR ligand (DR-L) expression (TRAIL, FasL, or TNF) is seen in responder PTEC by flow cytometry (surface or intracellular) or by ELISA (secreted into media). Moreover, target-induced apoptosis of PTEC responders was not prevented by inhibitors of DR-L, nor was it induced by addition of soluble DR-L.
Conclusion
Exposure of viable PTEC to apoptotic (but not necrotic) targets induces PTEC apoptosis via DR-dependent mechanisms. Surprisingly, target-induced apoptosis occurs in a ligand-independent manner, with recognition of apoptotic (but not necrotic) targets leading to DR-L-independent egagement of DRs. We hypothesize that PTEC injury in vivo is characterized by two distinct waves of cell death. In the 1st, PTEC death is the direct result of ischemic or other injury. In the 2nd, PTEC death is independent of injury, and the result of DR activation by recognition of adjacent dead or dying cells.
Funding
- Clinical Revenue Support