Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Acute kidney injury (AKI) presents significant morbidity, mortality, and healthcare costs, with limited therapeutic interventions.
• Reactive oxygen species (ROS) play a crucial role in the development of ischemic AKI.
• Stanniocalcin-1 (STC1) is known to suppress superoxide generation via uncoupling proteins (UCPs), offering protection against ischemia/reperfusion (I/R) kidney injury.

Purpose of the Study:

• To investigate the hypothesis that STC1 protects against I/R kidney injury through the activation of AMP-activated protein kinase (AMPK).

Main Methods:

• Comparative analysis of AMPK activity and STC expression in STC1 transgenic, wild-type (WT), STC1 knockout, and STC1/STC2 double-knockout mice.
• Assessment of kidney injury markers, AMPK activity, and expression of STC1, UCP2, and sirtuin 3 following I/R in WT mice with and without AMPK inhibition (compound C).
• In vitro studies using HEK cells treated with recombinant STC1 and/or compound C to evaluate AMPK activation and UCP2/sirtuin 3 expression.

Main Results:

• Baseline AMPK activity in kidneys correlated with STC expression levels across different mouse models.
• I/R injury in WT kidneys increased AMPK activity, STC1, UCP2, and sirtuin 3 expression.
• AMPK inhibition aggravated I/R kidney injury and diminished STC1-induced UCP2 and sirtuin 3 expression, while STC1 expression remained unaffected.
• STC1 knockout mice showed increased susceptibility to I/R, and AMPK inhibition in STC1 transgenic mice restored this susceptibility.

Conclusions:

• STC1 plays a critical role in activating AMPK within the kidney.
• AMPK activation mediates the protective effects of STC1 against I/R kidney injury by upregulating UCP2 and sirtuin 3.
• Targeting the STC1-AMPK pathway may offer a novel therapeutic strategy for ischemic AKI.