Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease.

The kidneys consume a large amount of energy to regulate volume status and blood pressure and to excrete uremic toxins. The identification of factors that cause energy mismatch in the setting of chronic kidney disease (CKD) and the development of interventions aimed at improving this mismatch are key research imperatives. Although the critical cellular energy sensor 5′- adenosine monophosphate( AMP)- activated protein kinase( AMPK) is known to be inactivated in CKD, the mechanism of AMPKdysregulation is unknown. In a mouse model of CKD, metabolome analysis confirmed a decrease in AMPKactivation in the kidneys despite a high AMP: ATP ratio, suggesting that AMPKdid not sense energy depletion. Similar AMPKinactivation was found in heart and skeletal muscle in CKD mice. Several uremic factors were shown to inactivate AMPKin vitro and in ex vivo preparations of kidney tissue. The specific AMPKactivator A-769662, which bypasses the AMP sensing mechanism, ameliorated fibrosis and improved energy status in the kidneys of CKD mice, whereas an AMP analog did not. We further demonstrated that a low-protein dietactivated AMPKindependent of the AMP sensing mechanism, leading to improvement in energy metabolism and kidney fibrosis. These results suggest that a failure to sense AMP is the key mechanism underlying the vicious cycle of energy depletion and CKD progression and direct AMPKactivation may be a novel therapeutic approach in CKD.