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Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser¹¹⁷⁷

¹Austin Research Institute, ²Department of Nephrology and ³Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria; ⁴St. Vincent’s Institute, Fitzroy, Victoria; and ⁵Commonwealth Scientific and Industrial Research Organisation Health Sciences and Nutrition, Parkville, Victoria, Australia

Submitted 20 December 2004 ; accepted in final form 19 May 2005

A fundamental aspect of acute renal ischemia is energy depletion, manifest as a falling level of ATP that is associated with a simultaneous rise in AMP. The energy sensor AMP-activated protein kinase (AMPK) is activated by a rising AMP-to-ATP ratio, but its role in acute renal ischemia is unknown. AMPK is activated in the ischemic heart and is reported to phosphorylate both endothelial nitric oxide synthase (eNOS) and acetyl-CoA carboxylase. To study activation of AMPK in acute renal ischemia, the renal pedicle of anesthetized Sprague-Dawley rats was cross-clamped for increasing time intervals. AMPK was strongly activated within 1 min and remained so after 30 min. However, despite the robust activation of AMPK, acute renal ischemia did not increase phosphorylation of the AMPK phosphorylation sites eNOS-Ser¹¹⁷⁷ or acetyl-CoA carboxylase-Ser⁷⁹. Activation of AMPK in bovine aortic endothelial cells by the ATP-depleting agent antimycin A and the antidiabetic drug phenformin also did not increase phosphorylation of eNOS-Ser¹¹⁷⁷, confirming that AMPK activation and phosphorylation of eNOS are dissociated in some situations. Immunoprecipitation studies demonstrated that the dissociation between AMPK activation and phosphorylation of eNOS-Ser¹¹⁷⁷ was not due to changes in the physical associations between AMPK, eNOS, or heat shock protein 90. In conclusion, acute renal ischemia rapidly activates the energy sensor AMPK, which is known to maintain ATP reserves during energy stress. The substrates it phosphorylates, however, are different from those in other organs such as the heart.

AMP-activated protein kinase; endothelial nitric oxide synthase; acetyl-CoA carboxylase; kidney

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