Abstract: FR-PO129
Stanniocalcin-1 Ameliorates Ischemia-Reperfusion Kidney Injury via Selective Activation of AMPK-a2
Session Information
- AKI: Mechanisms - II
November 04, 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
Authors
- Pan, Jenny S., Baylor College of Medicine, Houston, Texas, United States
- Li, Qingtian, Baylor College of Medicine, Houston, Texas, United States
- Sheikh-Hamad, David (Daud), Baylor College of Medicine, Houston, Texas, United States
Background
Acute kidney injury (AKI) is common and is associated with increased morbidity, mortality, and development/progression of chronic kidney disease. Currently, therapeutic options remain limited. AMPK activation has been found to protect from AKI. However, there are concerns about off target effects as AMPK is ubiquitously expressed and exert a multitude of regulatory effects. We previously showed that STC1 protects from ischemia-reperfusion (I/R) kidney injury through an AMPK-dependent pathway. In STC1 Tg kidneys, we observe preferential activation (phosphorylation) of the AMPK α2 isoform relative to the α1 isoform compared to WT kidneys. We hypothesize that kidney protection by STC1 is mediated through selective activation of the AMPKα2 isoform.
Methods
In the current experiments, we sought to determine kidney phenotype after I/R kidney injury in mice with transgenic overexpression of STC1 and inducible, kidney tubular epithelium-specific knockdown of AMPK a1 (STC1 Tg; AMPKa1f/f; Pax8rtTA; LC1-Cre; referred to as AMPKa1KO) or AMPK a2 (STC1 Tg; AMPKa2f/f; Pax8rtTA; LC1-Cre; referred to as AMPKa2KO); all on C57B/6 background. 10-12 week old mice were subjected to bilateral kidney I/R (clamping of renal pedicles for 30 min with non-traumatic vascular clamps). Mice were euthanized after 72 hours; blood and timed urine were collected for calculation of creatinine clearance, and kidneys were harvested for analyses.
Results
Using antibodies that recognize both α1 and α2 isoforms of the catalytic subunits of AMPK, we observed preferential phosphorylation of the α2 isoform in STC1 Tg kidneys compared with WT kidneys. Kidney tubule-specific knockdown of AMPK a2 in STC1 transgenic mice (AMPKa2KO) restored the susceptibility to I/R kidney injury (demonstrated by decreased creatinine clearance and urine output, and increased histologic injury and mitochondrial ROS). In contrast, kidney tubule-specific knockdown of AMPK a1 in STC1 transgenic mice (AMPKa1KO) had no significant effect on STC1-mediated kidney protection (preserved creatinine clearance, kidney morphology and urine output; less ROS production).
Conclusion
The data suggest that STC1 ameliorates ischemia-reperfusion kidney injury via an AMPK-a2-dependent pathway. Selective activation of the AMPK a2 isoform by STC1 may protect from AKI while minimizing off target effects of AMPK activation.
Funding
- Veterans Affairs Support