Abstract
AimActivation of the master energy-regulator AMP-activated protein kinase (AMPK) in the heart reduces the severity of ischemia-reperfusion injury (IRI) but the role of AMPK in renal IRI is not known. The aim of this study was to determine whether activation of AMPK by acute renal ischemia influences the severity of renal IRI.MethodsAMPK expression and activation and the severity of renal IRI was studied in mice lacking the AMPK β1 subunit and compared to wild type (WT) mice.ResultsBasal expression of activated AMPK, phosphorylayed at αThr172, was markedly reduced by 96% in AMPK-β1−/− mice. Acute renal ischaemia caused a 3.2-fold increase in α1-AMPK activity and a 2.5-fold increase in α2-AMPK activity (P<0.001) that was associated with an increase in AMPK phosphorylation of the AMPK-α subunit at Thr172 and Ser485, and increased inhibitory phosphorylation of the AMPK substrate acetyl-CoA carboxylase. After acute renal ischemia AMPK activity was reduced by 66% in AMPK-β1−/− mice compared with WT. There was no difference, however, in the severity of renal IRI at 24-hours between AMPK-β1−/− and WT mice, as measured by serum urea and creatinine and histological injury score. In the heart, macrophage migration inhibitory factor (MIF) released during IRI contributes to AMPK activation and protects from injury. In the kidney, however, no difference in AMPK activation by acute ischemia was observed between MIF−/− and WT mice. Compared with the heart, expression of the MIF receptor CD74 was found to be reduced in the kidney.ConclusionThe failure of AMPK activation to influence the outcome of IRI in the kidney contrasts with what is reported in the heart. This difference might be due to a lack of effect of MIF on AMPK activation and lower CD74 expression in the kidney.
Highlights
AMPK is a ubiquitously expressed, energy-sensing kinase that is activated during energy stress by an increase in cellular [AMP] [1]
AMPK is rapidly activated by acute renal ischemia [15] but whether this has an effect on the outcome the outcome of renal ischemia-reperfusion injury (IRI) is not known
The present study aims to determine the functional significance of AMPK activation in acute renal ischemia by determining the outcome of IRI in mice deficient for the AMPK b1 subunit (AMPK-b12/2 mice)
Summary
AMPK is a ubiquitously expressed, energy-sensing kinase that is activated during energy stress by an increase in cellular [AMP] [1]. In the ischemic heart the effect of AMPK activation is reported to be beneficial by preventing post-ischemic cardiac dysfunction, apoptosis, and injury [3,4,5,6]. These studies, have been contradicted by others, which showed that activation of AMPK in the ischemic heart has either no effect [7] or increases apoptosis [8]. AMPK is reported to be involved in a variety of physiological and pathological processes including ion transport [12], podocyte function [13] and diabetic renal hypertrophy [14]. AMPK is rapidly activated by acute renal ischemia [15] but whether this has an effect on the outcome the outcome of renal IRI is not known
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