Abstract: TH-PO1129
Kidney Protection during the AKI to CKD Transition: Post-translational Modifications Drive Peroxisome Activity and Cytoskeletal Rearrangements
Session Information
- CKD: Mechanisms - 1
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Author
- Pfister, Katherine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background
Acute Kidney injury (AKI) is an unfortunately frequent disease without an effective treatment. In many cases, AKI can progress to Chronic Kidney Disease (CKD) and in the worst-case scenario, End Stage Renal Disease (ESRD). To attenuate these transitions, we need a better understanding of the cellular mechanisms underlying damage and physiological changes as disease progresses. The most pronounced effect of AKI is on the Proximal Tubule Epithelial Cells (PTECs) which have the highest metabolic activity and are therefore most susceptible to damage after ischemia, sepsis, or transplant stress. This damage causes not only an increase in radical oxygen species and genetic reprogramming but also a significant change in the landscape of posttranslational modifications (PTMs).
Methods
With our collaborators, we performed targeted mass spectrometry and data-mining to understand the progressive changes in untreated AKI to CKD in murine kidneys. Following our recently published study on the protective effects of upregulated peroxisomal fatty acid oxidation (FAO) through dicarboxylic acid diet supplementation, we analyzed the long-term effects of Suberic Acid (DC8) on the AKI to CKD transition. Large classes of proteins can be modulated rapidly and reversibly through the activity of enzymes that ligate Posttranslational Modifications (PTMs) and we developed a list of candidate proteins that are significantly altered in DC8-fed mice exposed to a CKD model of injury.
Results
We chose to focus on the relationship between peroxisomal FAO enzymes and the resulting cytoskeletal changes that drive the fibrotic phenotype indicative of CKD. We identified a list of actin-binding proteins that are specifically succinylated at key residues when the DC8 treated mice are subjected to an in vivo model for CKD and we propose that the increased peroxisomal FAO has long-term protective effects maintaining the epithelial profile of PTECs after injury, preventing cell shedding, tubular collapse, and increased fibrotic scarring that are signs of worsening CKD and ESRD.
Conclusion
By understanding the cellular mechanisms of the AKI to CKD transition we can promote directed clinical trials to lessen the number of patients on lifetime dialysis and those requiring kidney transplants worldwide.
Funding
- NIDDK Support