Abstract: SA-PO0160
Recognition of Apoptotic Cells by Viable Proximal Tubular Epithelial Cells (PTEC) Induces Apoptotic Death That Is Inhibitable in a Casein Kinase 1 (CK1)-Dependent Manner
Session Information
- AKI: Mechanisms - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Dzielawa, Hannah, University of Illinois Chicago, Chicago, Illinois, United States
- Kumar, Sandeep, University of Illinois Chicago, Chicago, Illinois, United States
- Rana, Ajay, University of Illinois Chicago, Chicago, Illinois, United States
- Levine, Jerrold S., University of Illinois Chicago, Chicago, Illinois, United States
Background
We have shown that BU.MPT cells, a mouse kidney PTEC line, have distinct non-competing receptors for apoptotic and necrotic targets. Recognition of apoptotic, but not necrotic, targets induces apoptotic death of viable PTEC responders. Apoptosis occurs via the extrinsic pathway, with activation of caspase-8 leading to cleavage of BID into truncated BID (tBID), followed by activation of caspase-3. We previously generated a resistant line of BU.MPT (BU.MPTRES) which are resistant to the effects of apoptotic targets but undergo apoptosis normally to all other apoptotic stimuli.
Methods
Responder cells were BU.MPT, a conditionally immortalized mouse PTEC line. Studies used either the parent cell line (BU.MPT), which undergoes apoptosis after exposure to apoptotic targets, or a fully resistant line (BU.MPTRES) generated by repeated exposure to apoptotic targets. Targets were apoptotic cells, homologous (BU.MPT) or heterologous (DO11.10 lymphocytes).
Results
We show here that resistance of BU.MPTRES is the apparent result of phosphorylation of BID by CK1. Comparison of signaling events induced by apoptotic target exposure in BU.MPT vs. BU.MPTRES responders indicated that the acquired resistance of BU.MPTRES lies in cleavage of BID to tBID. After exposure to apoptotic targets, both BU.MPT and BU.MPTRES show caspase-8 cleavage, and consumption of the pro-survival inhibitory protein c-FLIP, but only BU.MPT show depletion of BID and appearance of tBID, followed by cleavage of caspase-3. Pharmacologic inhibition of CK1, but not CK2, rendered BU.MPTRES fully susceptible to the effects of targets, comparable to that of parent BU.MPT, including ~100% apoptotic death by 72 h after exposure, cleavage of BID into tBID, and cleavage of caspase 3. The effects of CK1 on BU.MPTRES were dose-dependent, but minimal for BU.MPT.
Conclusion
The death-inducing-death response of PTEC upon receptor-mediated recognition of apoptotic targets may be seen as an amplification of injury after the initial insult. Unlike the initial insult, which requires anticipation to inhibit, the death-inducing-death response can be interrupted after injury. Development of a pharmacologic means to activate CK1 offers the therapeutic potential to ameliorate the extent of acute kidney injury even after injury has occurred.
Funding
- Clinical Revenue Support