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bioRxiv · 10.1101/2023.08.09.552390

ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease

Yanagi, T.·Kikuchi, H.·Takeuchi, K.·Susa, K.·Mori, T.·Takahashi, N.·Suzuki, T.·Nakano, Y.·Fujiki, T.·Hara, Y.·Suzuki, S.·Mori, Y.·Ando, F.·Mandai, S.·Honda, S.·Torii, S.·Shimizu, S.·Rai, T.·Uchida, S.·Sohara, E.
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Abstract

AMP-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular adenosine monophosphate (AMP) levels result in AMPK activation through the binding of AMP to the {gamma}-subunit of AMPK. Recently, we reported that AMP-induced AMPK activation is impaired in the kidneys in chronic kidney disease (CKD) despite an increase in the AMP/ATP ratio. However, the mechanisms by which AMP sensing is disrupted in CKD are unclear. In this study, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPK{gamma}1 at Ser260/Thr262 promotes AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1-/- mice despite an increased AMP/ATP ratio. We also demonstrated that MK8722, an allosteric AMPK activator, activates AMPK in the kidneys of a CKD mouse model via a pathway that is independent of AMP sensing. MK8722 treatment significantly attenuates the deterioration of renal function in CKD and is a potential therapeutic option in CKD therapeutics.

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Yanagi, T., Kikuchi, H., Takeuchi, K., Susa, K., Mori, T., Takahashi, N., Suzuki, T., Nakano, Y., Fujiki, T., Hara, Y., Suzuki, S., Mori, Y., Ando, F., Mandai, S., Honda, S., Torii, S., Shimizu, S., Rai, T., Uchida, S., Sohara, E.. 2023-08-09. ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease. https://doi.org/10.1101/2023.08.09.552390

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