Succinylation of Park 7 Activates a Protective Metabolic Response to AKI
- AKI: Mechanisms - III
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Pfister, Katherine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Silva Barbosa, Anne Caroline, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Chiba, Takuto, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Goetzman, Eric S., Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States
- Sims-Lucas, Sunder, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Acute Kidney Injury (AKI) is extremely prevalent among hospitalizations and presents a significant risk for the development of chronic kidney disease and increased mortality. Ischemia caused by shock, trauma, and transplant are common causes of AKI. To attenuate AKI occurrence therapeutically we need a better understanding of the physiological and cellular mechanisms underlying damage. The most pronounced effect of AKI is on the Proximal Tubule Epithelial Cells (PTECs) which have the highest metabolic activity and are therefore most reliant on undisturbed blood flow and oxygen content.
We simulate AKI in vitro with hypoxia and glucose deprivation. Hypoxia signaling induces rapid posttranslational modifications (PTMs) on proteins. A growing list of PTMs have been identified and their effects described in AKI but among the understudied are succinylation and glycation.
We have previously shown a protective effect on PTECs after depletion of the desuccinylase Sirtuin 5, however Sirtuin 5 is not a druggable target. Mass spectrometry analysis of Sirtuin 5 knockout PTECs revealed changes in mitochondrial and peroxisomal activity and we suggest that this activity is modulated in part by the protective effects of the deglycase Park7. Park7 expression is decreased after Ischemia-Reperfusion Injury but increased in Sirtuin 5 knockout cells.
These data in combination with published results of Park7’s protective role in cardiovascular damage and chronic kidney disease lead us to hypothesize that Park7 may ameliorate oxidative damage resulting from AKI and prevent disease progression. We hope to harness this mechanism to develop novel therapies for AKI.
- NIDDK Support