自身免疫性肾小球疾病的靶向自噬。

IF 2.6 4区 医学 Q2 UROLOGY & NEPHROLOGY
Journal of Nephrology Pub Date : 2025-09-01 Epub Date: 2025-03-19 DOI:10.1007/s40620-025-02267-9
Claudio Ponticelli, Gabriella Moroni
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引用次数: 0

摘要

自噬是一种自然过程,细胞中受损或死亡的部分被清除并循环利用。自噬通常是指巨噬,巨噬与微自噬和伴侣介导的自噬是三种自噬类型之一。自噬由腺苷单磷酸活化蛋白激酶(AMPK)激活,由哺乳动物雷帕霉素靶蛋白(mTOR)通过干扰unc -51样激酶1 (ULK1)抑制。自噬失调与自身免疫性肾小球疾病密切相关。上调的自噬可以诱导炎症,激活先天免疫和适应性免疫。然而,在缺血性或内毒素急性肾损伤(AKI)期间,自噬也可能对足细胞起保护作用,增强内皮细胞功能,保护近端小管上皮细胞。羟氯喹(Hydroxychloroquine, HCQ)可下调增加的自噬,广泛应用于狼疮性肾炎。HCQ引起碱化,导致溶酶体空泡化并抑制其功能。通过抑制自噬活性,HCQ可以减少炎症和先天免疫,抑制T细胞的活化,恢复T辅助17/T调节平衡,限制促炎细胞因子的产生,调节共刺激分子。这减少了耀斑的风险,节省了糖皮质激素的剂量,改善狼疮活动,并防止抗磷脂抗体的血栓形成作用。最近的研究表明,HCQ还可以减少IgA肾病(IgAN)和膜性肾病(MN)的蛋白尿。改善线粒体功能或增强自噬的药物,如二甲双胍、钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂或mTOR抑制剂,可能对足细胞起到保护作用,并减少MN或局灶节段性肾小球硬化(FSGS)患者的蛋白尿。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting autophagy in autoimmune glomerular diseases.

Autophagy is a natural process whereby damaged or dying parts of a cell are eliminated and recycled. The term autophagy usually refers to macroautophagy, which is one of three types of autophagy, alongside microautophagy and chaperone-mediated autophagy. Autophagy is activated by adenosine monophosphate-activated protein kinase (AMPK) and inhibited by mammalian target of rapamycin (mTOR) through their interference with Unc-51-like kinase 1 (ULK1). Dysregulated autophagy is deeply involved in autoimmune glomerular diseases. Upregulated autophagy can induce inflammation and activate innate and adaptive immunity. However, autophagy may also exert a protective role on podocytes, enhance endothelial cell function, and preserve proximal tubular epithelial cells during ischemic or endotoxic acute kidney injury (AKI). Hydroxychloroquine (HCQ) can downregulate increased autophagy and is widely used in lupus nephritis. HCQ causes alkalinization, which results in vacuolization of lysosomes and inhibition of their functions. By inhibiting autophagic activity, HCQ may reduce inflammation and innate immunity, inhibit the activation of T cells, restore the T helper 17/T regulator balance, restrict the production of pro-inflammatory cytokines, and modulate co-stimulatory molecules. This reduces the risk of flares, spares the dosage of glucocorticoids, improves lupus activity, and prevents the thrombotic effects of anti-phospholipid antibodies. Recent studies showed that HCQ can also reduce proteinuria in IgA nephropathy (IgAN) and membranous nephropathy (MN). Drugs that improve mitochondrial function or enhance autophagy, such as metformin, sodium-glucose co-transporter 2 (SGLT2) inhibitors or mTOR inhibitors, may exert protective effects on podocytes and reduce proteinuria in MN or focal segmental glomerulosclerosis (FSGS).

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来源期刊
Journal of Nephrology
Journal of Nephrology 医学-泌尿学与肾脏学
CiteScore
5.60
自引率
5.90%
发文量
289
审稿时长
3-8 weeks
期刊介绍: Journal of Nephrology is a bimonthly journal that considers publication of peer reviewed original manuscripts dealing with both clinical and laboratory investigations of relevance to the broad fields of Nephrology, Dialysis and Transplantation. It is the Official Journal of the Italian Society of Nephrology (SIN).
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