Dephosphorylation of AMP-activated protein kinase exacerbates ischemia/reperfusion-induced acute kidney injury via mitochondrial dysfunction

Kidney tubular epithelial cells are high energy-consuming epithelial cells that depend mainly on fatty acid oxidation for an energy supply. AMP-activated protein kinase (AMPK) is a key regulator of energy production in most cells, but the function of AMPK in tubular epithelial cells in acute kidney disease is unclear. Here, we found a rapid decrease in Thr172-AMPKa phosphorylation after ischemia/reperfusion in both in vivo and in vitro models. Mice with kidney tubular epithelial cell-specific AMPKa deletion exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after ischemia/reperfusion. AMPKa deficiency was accompanied by the accumulation of lipid droplets in the kidney tubules and the elevation of ceramides and free fatty acid levels following ischemia/reperfusion injury. Mechanistically, ischemia/reperfusion triggered ceramide production and activated protein phosphatase PP2A, which dephosphorylated Thr172-AMPKa. Decreased AMPK activity autophagy and impeded clearance of the dysfunctional mitochondria. Targeting the PP2A-AMPK axis by the dephosphorylation and promoting the mitophagy process. Thus, our study reveals that AMPKa plays an important role in protecting against tubular epithelial cell injury in for acute kidney injury treatment.

Automated summary

This study reveals that AMP-activated protein kinase (AMPK) plays an important protective role in tubular epithelial cells during acute kidney injury. The deficiency of AMPK leads to lipid droplet accumulation and elevated levels of ceramides and free fatty acids in the kidney tubules, resulting in worsened kidney impairment.