ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease
Year: 2024
Type: article
Abstract: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular AMP levels result in AMPK activation through the binding of AMP to the γ-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. Here, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPKγ1 at Ser260/Thr262 promoting AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1 knockout mice despite an increased AMP/ATP ratio. ULK1 expression is markedly downregulated in CKD kidneys, leading to AMP sensing failure. Additionally, MK8722, an allosteric AMPK activator, stimulated AMPK in the kidneys of a CKD mouse model (5/6th nephrectomy) via a pathway that is independent of AMP sensing. Thus, our study shows that MK8722 treatment significantly attenuates the deterioration of kidney function in CKD and may be a potential therapeutic option in CKD therapeutics.
Source: Kidney International
Authors: Tomoki Yanagi, Hiroaki Kikuchi, Koh Takeuchi, Koichiro Susa, Takayasu Mori, Motoko Chiga, Kouhei Yamamoto, Asuka Furukawa, Takumi Kanazawa, Yuki Kato, Naohiro Takahashi, Takefumi Suzuki, Yutaro Mori, Benjamin C. Carter, Makiko Mori, Yuta Nakano, Tamami Fujiki, Yu Hara, Soichiro Suzuki, Fumiaki Ando, Shintaro Mandai, Shinya Honda, Satoru Torii, Shigeomi Shimizu, Hajime Tanaka, Yasuhisa Fujii, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,500
Awards: 腎臓オルガノイドを用いた腎線維化修飾遺伝子の探索, Investigation of the regulatory mechanism of renal fibrosis using forward genetics with renal organoids, Investigation of aggravating factors for renal fibrosis using kidney organoids, Novel therapies for chemotherapy-induced fluid disorders via targeting water channels, 線維化レポーター腎臓オルガノイドによるCKD増悪因子の新規スクリーニング, Non-canonical beta-catenin phosphorylation and regulation of gene expression in chronic kidney disease, G4571843634, Elucidation of physiological functions of Ulk1 phosphorylation which acts as a molecular switch leading to alternative autophagy, G4882170996, G4890024836, エネルギー感知機構の破綻による慢性腎臓病の線維化進行機序解明と治療法開発, Dissecting Pathogenic PKA Signaling Pathways and Advancing Targeted Therapeutic Strategies, Elucidation of molecular pathogenesis and development of novel therapeutic strategy of energy-sensing failure of AMPK in chronic kidney disease, G5912327695, G6332709248, Application of AKAPs-PKA disruptors in the treatment of PKA-related diseases, G6441411564, Elucidating the mechanism of blood-brain barrier breakdown and cognitive dysfunction in chronic kidney disease, G6567422089, Non-canonical beta-catenin phosphorylation and regulation of gene expression in polycystic kidney disease, 遺伝性腎線維化症ネフロン癆の病態解明と新規治療法開発, G7214193964, G769247701, G833514557
OpenAlex ID: W4403548764