Augmenter of liver regeneration knockout aggravates tubular ferroptosis and macrophage activation by regulating carnitine palmitoyltransferase-1A-induced lipid metabolism in diabetic nephropathy

IF 5.6 2区医学 Q1 PHYSIOLOGY Acta Physiologica Pub Date : 2024-05-20 DOI:10.1111/apha.14159

Yuanyuan Zhang, Zheng Zhang, Lili Huang, Chunxia Wang, Pengfei Yang, Ling Zhang, Xiaohui Liao

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Abstract

Aim

Ferroptosis is a novel type of programmed cell death that performs a critical function in diabetic nephropathy (DN). Augmenter of liver regeneration (ALR) exists in the inner membrane of mitochondria, and inhibits inflammation, apoptosis, and oxidative stress in acute kidney injury; however, its role in DN remains unexplored. Here, we aimed to identify the role of ALR in ferroptosis induction and macrophage activation in DN.

Methods

The expression of ALR was examined in DN patients, db/db DN mice, and HK-2 cells treated with high glucose (HG). The effects of ALR on ferroptosis and macrophage activation were investigated with ALR conditional knockout, lentivirus transfection, transmission electron microscopy, qRT-PCR and western blotting assay. Mass spectrometry and rescue experiments were conducted to determine the mechanism of ALR.

Results

ALR expression was reduced in the kidney tissues of DN patients and mice, serum of DN patients, and HG-HK-2 cells. Moreover, the inhibition of ALR promoted ferroptosis, macrophage activation, and DN progression. Mechanistically, ALR can directly bind to carnitine palmitoyltransferase-1A (CPT1A), the key rate-limiting enzyme of fatty acid oxidation (FAO), and inhibit the expression of CPT1A to regulate lipid metabolism involving FAO and lipid droplet-mitochondrial coupling in DN.

Conclusion

Taken together, our findings revealed a crucial protective role of ALR in ferroptosis induction and macrophage activation in DN and identified it as an alternative diagnostic marker and therapeutic target for DN.

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通过调节肉碱棕榈酰基转移酶-1A诱导的糖尿病肾病脂质代谢，肝脏再生增强基因敲除可加重肾小管铁变态反应和巨噬细胞活化。

目的：铁凋亡是一种新型的程序性细胞死亡，在糖尿病肾病（DN）中发挥着关键作用。肝脏再生促进剂（ARR）存在于线粒体内膜中，可抑制急性肾损伤中的炎症、细胞凋亡和氧化应激；但它在糖尿病肾病中的作用仍有待探索。在此，我们旨在确定 ALR 在 DN 中诱导铁变态反应和巨噬细胞活化中的作用：方法：在 DN 患者、db/db DN 小鼠和经高糖（HG）处理的 HK-2 细胞中检测 ALR 的表达。通过 ALR 条件性基因敲除、慢病毒转染、透射电子显微镜、qRT-PCR 和 Western 印迹检测，研究了 ALR 对铁突变和巨噬细胞活化的影响。结果发现，ALR在肾脏中的表达量减少：结果：ALR在DN患者和小鼠肾脏组织、DN患者血清以及HG-HK-2细胞中的表达均降低。结果发现：ALR在DN患者和小鼠的肾脏组织、血清以及HG-HK-2细胞中的表达减少，而且抑制ALR可促进铁变态反应、巨噬细胞活化和DN进展。从机理上讲，ALR可直接与脂肪酸氧化（FAO）的关键限速酶肉碱棕榈酰转移酶-1A（CPT1A）结合，抑制CPT1A的表达，从而调控DN中涉及FAO和脂滴-线粒体偶联的脂质代谢：综上所述，我们的研究结果揭示了 ALR 在 DN 中诱导铁变态反应和激活巨噬细胞的关键保护作用，并将其确定为 DN 的替代诊断标志物和治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Physiologica 医学-生理学

CiteScore

11.80

自引率

15.90%

发文量

182

审稿时长

4-8 weeks

期刊介绍： Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.