A novel therapeutic target for kidney diseases: Lessons learned from starvation response

IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacology & Therapeutics Pub Date : 2024-02-01 DOI:10.1016/j.pharmthera.2024.108590
Kosuke Yamahara, Mako Yasuda-Yamahara, Shinji Kume
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Abstract

The prevalence of chronic kidney disease (CKD) is increasing worldwide, making the disease an urgent clinical challenge. Caloric restriction has various anti-aging and organ-protective effects, and unraveling its molecular mechanisms may provide insight into the pathophysiology of CKD. In response to changes in nutritional status, intracellular nutrient signaling pathways show adaptive changes. When nutrients are abundant, signals such as mechanistic target of rapamycin complex 1 (mTORC1) are activated, driving cell proliferation and other processes. Conversely, others, such as sirtuins and AMP-activated protein kinase, are activated during energy scarcity, in an attempt to compensate. Autophagy, a cellular self-maintenance mechanism that is regulated by such signals, has also been reported to contribute to the progression of various kidney diseases. Furthermore, in recent years, ketone bodies, which have long been considered to be detrimental, have been reported to play a role as starvation signals, and thereby to have renoprotective effects, via the inhibition of mTORC1. Therefore, in this review, we discuss the role of mTORC1, which is one of the most extensively studied nutrient-related signals associated with kidney diseases, autophagy, and ketone body metabolism; and kidney energy metabolism as a novel therapeutic target for CKD.

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肾脏疾病的新型治疗靶点:从饥饿反应中汲取的经验教训
慢性肾脏病(CKD)的发病率在全球范围内不断上升,使该疾病成为一项紧迫的临床挑战。热量限制具有多种抗衰老和器官保护作用,揭示其分子机制可能有助于深入了解慢性肾脏病的病理生理学。为应对营养状况的变化,细胞内营养信号通路会发生适应性变化。当营养物质丰富时,雷帕霉素复合体 1(mTORC1)等信号被激活,推动细胞增殖和其他过程。相反,其他信号,如sirtuins和AMP激活的蛋白激酶,则会在能量匮乏时被激活,试图进行补偿。自噬是一种受此类信号调控的细胞自我维护机制,也有报道称它是导致各种肾脏疾病恶化的原因之一。此外,近年来有报道称,长期以来一直被认为有害的酮体可作为饥饿信号发挥作用,从而通过抑制 mTORC1 发挥保护肾脏的作用。因此,在这篇综述中,我们将讨论 mTORC1 的作用(mTORC1 是与肾脏疾病、自噬和酮体代谢有关的营养相关信号中研究最为广泛的信号之一),以及肾脏能量代谢作为 CKD 新型治疗靶点的作用。
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来源期刊
CiteScore
23.00
自引率
0.70%
发文量
222
审稿时长
90 days
期刊介绍: Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.
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