Dihydrolipoamide S-acetyltransferase activation alleviates diabetic kidney disease via AMPK-autophagy axis and mitochondrial protection

IF 6.4 2区 医学 Q1 MEDICAL LABORATORY TECHNOLOGY Translational Research Pub Date : 2024-10-09 DOI:10.1016/j.trsl.2024.09.005
Peihui Zhou, Ning Wang, Sijia Lu, Jie Xiong, Yao Zhang, Quanxin Jiang, Qiqi Qian, Qian Zhou, Junli Liu, Suzhen Chen
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Abstract

Diabetic kidney disease (DKD), a severe complication of diabetes marked by deregulated glucose metabolism, remains enigmatic in its pathogenesis. Herein, we delved into the functional role of Dihydrolipoamide S-acetyltransferase (DLAT), a pivotal E2 component of the pyruvate dehydrogenase complex (PDC), in the context of DKD. Our findings revealed a downregulation of DLAT in the kidneys of diabetic patients, correlating inversely with kidney function. Parallel downregulation was observed in both high-fat diet/streptozotocin (HFD/STZ) and db/db mouse models, as well as in human proximal tubular epithelial cells (HK-2) cultured under hyperglycemic conditions. To further elucidate the role of endogenous DLAT in DKD, we employed genetic ablation of Dlat in mouse models. Dlat haploinsufficient mice exhibited exacerbated renal dysfunction, structural damage, fibrosis, and mitochondrial dysfunction under DKD conditions. Consistent with these findings, modulation of DLAT expression in HK-2 cells highlighted its influence on fibrosis, with overexpression attenuating Fibronectin and Collagen I levels, while downregulation exacerbated fibrosis. Mechanistically, we discovered that DLAT activates mitochondria autophagy through the Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway, thereby mitigating mitochondrial dysfunction associated with DKD progression. Inhibition of AMPK abrogated the protective effects of DLAT against mitochondrial dysfunction and DKD. Notably, we identified Hyperforin (HPF), a phytochemical, as a potential therapeutic agent. HPF activates DLAT and AMPK, subsequently ameliorating renal dysfunction, injuries, and fibrosis in both in vivo and in vitro models. In summary, our study underscores the pivotal role of DLAT and AMPK in kidney health and highlights the therapeutic potential of HPF in treating DKD.
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二氢脂酰胺 S-乙酰转移酶活化可通过 AMPK 自噬轴和线粒体保护缓解糖尿病肾病
糖尿病肾病(DKD)是糖尿病的一种严重并发症,以糖代谢紊乱为特征,其发病机制至今仍是一个谜。在此,我们深入研究了二氢脂酰胺 S-乙酰转移酶(DLAT)在 DKD 中的功能作用,DLAT 是丙酮酸脱氢酶复合物(PDC)的关键 E2 组成部分。我们的研究结果表明,糖尿病患者肾脏中的 DLAT 下调,与肾功能成反比。在高脂饮食/链脲佐菌素(HFD/STZ)和 db/db 小鼠模型中,以及在高血糖条件下培养的人类近端肾小管上皮细胞(HK-2)中,都观察到了类似的下调现象。为了进一步阐明内源性 DLAT 在 DKD 中的作用,我们在小鼠模型中采用了基因消减 Dlat 的方法。在 DKD 条件下,Dlat 单倍性不足的小鼠表现出加剧的肾功能障碍、结构损伤、纤维化和线粒体功能障碍。与这些发现相一致的是,调节 HK-2 细胞中 DLAT 的表达突显了它对纤维化的影响,过表达可减轻纤连蛋白和胶原 I 的水平,而下调则会加剧纤维化。从机理上讲,我们发现DLAT可通过5'-单磷酸腺苷(AMP)激活的蛋白激酶(AMPK)信号通路激活线粒体自噬,从而缓解与DKD进展相关的线粒体功能障碍。抑制 AMPK 会减弱 DLAT 对线粒体功能障碍和 DKD 的保护作用。值得注意的是,我们发现一种植物化学物质--Hyperforin(HPF)是一种潜在的治疗药物。HPF 可激活 DLAT 和 AMPK,从而改善体内和体外模型中的肾功能障碍、损伤和纤维化。总之,我们的研究强调了 DLAT 和 AMPK 在肾脏健康中的关键作用,并突出了 HPF 治疗 DKD 的潜力。
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来源期刊
Translational Research
Translational Research 医学-医学:内科
CiteScore
15.70
自引率
0.00%
发文量
195
审稿时长
14 days
期刊介绍: Translational Research (formerly The Journal of Laboratory and Clinical Medicine) delivers original investigations in the broad fields of laboratory, clinical, and public health research. Published monthly since 1915, it keeps readers up-to-date on significant biomedical research from all subspecialties of medicine.
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