Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression
Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression
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DOI：
10.1111/gtc.12989
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发表时间：
2022-11
期刊：
影响因子：
2.1
通讯作者：
Tomoki Yanagi;Hiroaki Kikuchi;K. Susa;Naohiro Takahashi;Hiroki Bamba;Takefumi Suzuki;Y. Nakano;Tamami Fujiki;Yutaro Mori;Fumiaki Ando;Shintaro Mandai;Takayasu Mori;Koh Takeuchi;S. Honda;S. Torii;S. Shimizu;T. Rai;S. Uchida;E. Sohara
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作者：
Tomoki Yanagi;Hiroaki Kikuchi;K. Susa;Naohiro Takahashi;Hiroki Bamba;Takefumi Suzuki;Y. Nakano;Tamami Fujiki;Yutaro Mori;Fumiaki Ando;Shintaro Mandai;Takayasu Mori;Koh Takeuchi;S. Honda;S. Torii;S. Shimizu;T. Rai;S. Uchida;E. Sohara
慢性肾脏疾病（CKD）中AMP活化蛋白激酶（AMPK）失活导致肾脏能量状态恶化，构成CKD恶化的恶性循环。Unc‐51‐like kinase 1 （ULK1）被认为是AMPK的下游分子；然而，最近有报道称AMPK的活性可以被ULK1反过来调节。我们发现CKD小鼠肾脏AMPK和ULK1活性降低。然而，ULK1是否以及如何参与CKD恶化的潜在机制仍然未知。在这项研究中，我们使用ULK1敲除小鼠研究了ULK1在CKD中的作用。Ulk1−/−小鼠CKD模型表现出明显的肾功能恶化和肾纤维化恶化。在Ulk1−/−小鼠CKD模型的肾脏中，可以观察到AMPK的减少及其下游β -氧化，导致AMP/ATP比率增加的能量赤字。此外，与对照组野生型小鼠相比，正常肾功能的Ulk1−/−小鼠肾脏AMPK信号传导减少，表明Ulk1缺乏抑制了肾脏AMPK活性。这项研究首次提出ULK1作为CKD治疗的新治疗靶点，它调节肾脏中AMPK的活性。
AMP‐activated protein kinase (AMPK) inactivation in chronic kidney disease (CKD) leads to energy status deterioration in the kidney, constituting the vicious cycle of CKD exacerbation. Unc‐51‐like kinase 1 (ULK1) is considered a downstream molecule of AMPK; however, it was recently reported that the activity of AMPK could be regulated by ULK1 conversely. We demonstrated that AMPK and ULK1 activities were decreased in the kidneys of CKD mice. However, whether and how ULK1 is involved in the underlying mechanism of CKD exacerbation remains unknown. In this study, we investigated the ULK1 involvement in CKD, using ULK1 knockout mice. The CKD model of Ulk1−/− mice exhibited significantly exacerbated renal function and worsening renal fibrosis. In the kidneys of the CKD model of Ulk1−/− mice, reduced AMPK and its downstream β‐oxidation could be observed, leading to an energy deficit of increased AMP/ATP ratio. In addition, AMPK signaling in the kidney was reduced in control Ulk1−/− mice with normal renal function compared to control wild‐type mice, suggesting that ULK1 deficiency suppressed AMPK activity in the kidney. This study is the first to present ULK1 as a novel therapeutic target for CKD treatment, which regulates AMPK activity in the kidney.