FGF21和自噬协同对抗衰老和肥胖期间的肾脏疾病进展。

IF 14.6 1区 生物学 Q1 CELL BIOLOGY Autophagy Pub Date : 2024-03-01 Epub Date: 2023-09-24 DOI:10.1080/15548627.2023.2259282
Satoshi Minami, Shinsuke Sakai, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Atsushi Takahashi, Jun Matsuda, Hiroaki Yonishi, Jun Nakamura, Shihomi Maeda, Sho Matsui, Isao Matsui, Yoshitaka Isaka
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引用次数: 0

摘要

慢性肾脏病(CKD)已在全球范围内流行,部分原因是老年人和肥胖人口的增加。大细胞自噬/自噬抵消CKD进展,而自噬由于衰老和肥胖期间溶酶体负担过重而停滞,从而促进CKD进展。因此,为了预防CKD在衰老和肥胖过程中的进展,阐明自噬停滞的补偿机制很重要。我们最近发现,FGF21(成纤维细胞生长因子21)是一种延长寿命和代谢激素,是由肾近端小管上皮细胞(PTECs)的自噬缺陷诱导的;然而,其病理生理作用仍不确定。在这里,我们研究了FGF21和自噬之间的相互作用,以及衰老和肥胖期间肾脏中内源性FGF21的直接作用,使用24岁时PTEC特异性FGF21-和/或atg5缺陷小鼠 月(年龄)或在高脂肪饮食(肥胖)条件下。年轻小鼠中PTEC特异性FGF21的缺乏由于自噬需求的增加而增加了自噬流量,而FGF21缺乏的老年或肥胖小鼠由于异常自噬引起的溶酶体负担加重而加剧了自噬停滞。FGF21由自噬缺陷强烈诱导,与atg5缺陷小鼠相比,衰老或肥胖的PTEC特异性FGF21-和atg5双重缺陷小鼠的肾脏组织学恶化。双缺陷小鼠的线粒体功能受到严重干扰,同时氧化应激加剧,TFAM(转录因子A,线粒体)下调。这些结果表明,FGF21是由自噬障碍强烈诱导的,并通过减轻自噬停滞和维持线粒体稳态来防止CKD在衰老和肥胖过程中的进展,这将为CKD的新治疗铺平道路。
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FGF21 and autophagy coordinately counteract kidney disease progression during aging and obesity.

Chronic kidney disease (CKD) has reached epidemic proportions worldwide, partly due to the increasing population of elderly and obesity. Macroautophagy/autophagy counteracts CKD progression, whereas autophagy is stagnated owing to lysosomal overburden during aging and obesity, which promotes CKD progression. Therefore, for preventing CKD progression during aging and obesity, it is important to elucidate the compensation mechanisms of autophagy stagnation. We recently showed that FGF21 (fibroblast growth factor 21), which is a prolongevity and metabolic hormone, is induced by autophagy deficiency in kidney proximal tubular epithelial cells (PTECs); however, its pathophysiological role remains uncertain. Here, we investigated the interplay between FGF21 and autophagy and the direct contribution of endogenous FGF21 in the kidney during aging and obesity using PTEC-specific fgf21- and/or atg5-deficient mice at 24 months (aged) or under high-fat diet (obese) conditions. PTEC-specific FGF21 deficiency in young mice increased autophagic flux due to increased demand of autophagy, whereas fgf21-deficient aged or obese mice exacerbated autophagy stagnation due to severer lysosomal overburden caused by aberrant autophagy. FGF21 was robustly induced by autophagy deficiency, and aged or obese PTEC-specific fgf21- and atg5-double deficient mice deteriorated renal histology compared with atg5-deficient mice. Mitochondrial function was severely disturbed concomitant with exacerbated oxidative stress and downregulated TFAM (transcription factor A, mitochondrial) in double-deficient mice. These results indicate that FGF21 is robustly induced by autophagy disturbance and protects against CKD progression during aging and obesity by alleviating autophagy stagnation and maintaining mitochondrial homeostasis, which will pave the way to a novel treatment for CKD.

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来源期刊
Autophagy
Autophagy 生物-细胞生物学
CiteScore
21.30
自引率
2.30%
发文量
277
审稿时长
1 months
期刊介绍: Autophagy is a peer-reviewed journal that publishes research on autophagic processes, including the lysosome/vacuole dependent degradation of intracellular material. It aims to be the premier journal in the field and covers various connections between autophagy and human health and disease, such as cancer, neurodegeneration, aging, diabetes, myopathies, and heart disease. Autophagy is interested in all experimental systems, from yeast to human. Suggestions for specialized topics are welcome. The journal accepts the following types of articles: Original research, Reviews, Technical papers, Brief Reports, Addenda, Letters to the Editor, Commentaries and Views, and Articles on science and art. Autophagy is abstracted/indexed in Adis International Ltd (Reactions Weekly), EBSCOhost (Biological Abstracts), Elsevier BV (EMBASE and Scopus), PubMed, Biological Abstracts, Science Citation Index Expanded, Web of Science, and MEDLINE.
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