Lactate-triggered histone lactylation contributes to podocyte epithelial-mesenchymal transition in diabetic nephropathy in mice

IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ting Zheng , Yan-Ping Gu , Jiang-Meng Wang , Ting-Ting Huang , Ling-Shan Gou , Yao-Wu Liu
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Abstract

Diabetic nephropathy (DN) closely relates to morphological and functional changes of podocytes, and anaerobic glycolysis represents the predominant energy source of podocytes. However, it is unknown whether lactate accumulation in chronic high glucose causes epithelial-mesenchymal transition (EMT) of podocytes through lactate-derived histone lysine lactylation (HKla). Lactate levels increased in high glucose-stimulated mouse podocyte cell line MPC and blood and the kidney of diabetic mice. High glucose or exogenous lactate decreased nephrin levels while increased collagen IV and HKla levels in MPC, but co-treatment with oxamate or dichloroacetate reduced lactate levels and alleviated the decreases in nephrin and zonula occludens- 1 levels and the increases in collagen IV and α-smooth muscle actin as well as HKla levels in high glucose-cultured MPC. However, co-treatment with rotenone diversely affected these indices. Eleven intersection genes were screened in lactate raising and lowering interventions in podocytes using RNA sequencing and four genes were validated by qPCR. Furthermore, lactate-lowering treatments attenuated renal functions, EMT, and histone lactylation in the kidney of diabetic mice. Additionally, the increased lactate might result from the upregulated monocarboxylate transporter 2 in the mitochondria and the decreased pyruvate dehydrogenase activity. Together, we reveal the role of histone lactylation in driving the EMT phenotype of podocytes in chronic high glucose state, subsequently promoting the pathological process of DN. Our study provides a reference for the study of the relationship between lactate-induced histone lactylation modification and diabetic complications.

Abstract Image

乳酸触发的组蛋白乳酸化有助于糖尿病肾病小鼠足细胞上皮-间质转化。
糖尿病肾病与足细胞的形态和功能变化密切相关,而厌氧糖酵解是足细胞的主要能量来源。然而,慢性高糖的乳酸积累是否会通过乳酸衍生的组蛋白赖氨酸乳酸化(HKla)导致足细胞的上皮-间质转化(EMT)尚不清楚。高糖刺激小鼠足细胞细胞系MPC及糖尿病小鼠血液和肾脏乳酸水平升高。高糖或外源性乳酸降低了MPC中nephrin水平,升高了胶原IV和HKla水平,但与草酸酯或二氯乙酸共处理降低了MPC中乳酸水平,缓解了高糖培养MPC中nephrin和occludens- 1水平的下降以及胶原IV和α-平滑肌肌动蛋白和HKla水平的升高。然而,与鱼藤酮共处理对这些指标的影响不同。利用RNA测序技术筛选了11个与足细胞乳酸升高和降低干预相关的交叉基因,并利用qPCR技术对其中4个基因进行了验证。此外,降低乳酸浓度可以减轻糖尿病小鼠的肾功能、EMT和肾脏组蛋白乳酸化。此外,乳酸的增加可能是由于线粒体中单羧酸转运蛋白2的上调和丙酮酸脱氢酶活性的降低。我们共同揭示了组蛋白乳酸化在慢性高糖状态下驱动足细胞EMT表型,进而促进DN病理过程中的作用。本研究为研究乳酸诱导的组蛋白乳酸化修饰与糖尿病并发症的关系提供了参考。
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
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
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