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

IF 14.8 1区医学 Q1 UROLOGY & NEPHROLOGY

Kidney international Pub Date : 2024-10-18 DOI:10.1016/j.kint.2024.08.024

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 , Eisei Sohara

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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.

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ULK1调控AMPK的AMP感应及其在慢性肾病治疗中的应用。

单磷酸腺苷（AMP）活化蛋白激酶（AMPK）是一种参与能量平衡的中心激酶。细胞内 AMP 水平的增加会通过 AMP 与 AMPK γ 亚基的结合导致 AMPK 的活化。最近，我们报告说，尽管 AMP/ATP 比率增加，但在慢性肾脏病（CKD）患者的肾脏中，AMP 诱导的 AMPK 激活功能受损。然而，CKD 中 AMP 感知受到破坏的机制尚不清楚。在这里，我们确定了能量平衡的机制，其中Unc-51样激酶1（ULK1）依赖于AMPKγ1在Ser260/Thr262处的磷酸化促进了AMPK对AMP的敏感性。在 Ulk1 基因敲除的小鼠中，尽管 AMP/ATP 比率增加，但 AMP 对 AMPK 的活化却受到了影响。在慢性肾脏病肾脏中，ULK1的表达明显下调，导致AMP感应失灵。此外，异位 AMPK 激活剂 MK8722 可通过独立于 AMP 感受的途径刺激 CKD 小鼠模型（5/6 次肾切除）肾脏中的 AMPK。因此，我们的研究表明，MK8722 治疗能明显减轻慢性肾功能衰竭患者肾功能的恶化，可能是慢性肾功能衰竭治疗中的一种潜在治疗选择。

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来源期刊

Kidney international 医学-泌尿学与肾脏学

CiteScore

23.30

自引率

3.10%

发文量

490

审稿时长

3-6 weeks

期刊介绍： Kidney International (KI), the official journal of the International Society of Nephrology, is led by Dr. Pierre Ronco (Paris, France) and stands as one of nephrology's most cited and esteemed publications worldwide. KI provides exceptional benefits for both readers and authors, featuring highly cited original articles, focused reviews, cutting-edge imaging techniques, and lively discussions on controversial topics. The journal is dedicated to kidney research, serving researchers, clinical investigators, and practicing nephrologists.