Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes
Hyperglycemia alters mitochondrial respiration efficiency and mitophagy in human podocytes
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DOI：
10.1016/j.yexcr.2021.112758
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发表时间：
2021-08-26
影响因子：
3.7
通讯作者：
Piwkowska, Agnieszka
中科院分区：
文献类型：
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作者：
Audzeyenka, Irena;Rachubik, Patrycja;Piwkowska, Agnieszka
足细胞构成肾小球滤过屏障的外层。它们的能量需求强烈依赖于有效的氧化呼吸，这与线粒体动力学密切相关。我们假设高血糖调节肾小球和足细胞的能量代谢，并有助于糖尿病肾病的发展。我们发现，在高葡萄糖浓度（30 mM； HG）下培养的糖尿病大鼠肾小球和人足细胞的耗氧率严重降低。在这些模型中，所有线粒体呼吸参数，包括基础呼吸和最大呼吸、ATP生成和备用呼吸能力，均显著降低。HG处理的足细胞线粒体网络呈碎片化，线粒体融合标记MEN1、MFN2和OPA1的表达减少，裂变标记DRP1的活性增加。我们发现，在hg处理的足细胞中，线粒体生物发生标志物，如PGC-1 α和TFAM下降。此外，在这些细胞中，PINK1/帕金森依赖性的有丝分裂被抑制。这些结果提供了高血糖损害线粒体动力学和周转的证据，这可能是肾小球和足细胞线粒体呼吸参数显着恶化的基础。
Podocytes constitute the outer layer of the renal glomerular filtration barrier. Their energy requirements strongly depend on efficient oxidative respiration, which is tightly connected with mitochondrial dynamics. We hypothesized that hyperglycemia modulates energy metabolism in glomeruli and podocytes and contributes to the development of diabetic kidney disease. We found that oxygen consumption rates were severely reduced in glomeruli from diabetic rats and in human podocytes that were cultured in high glucose concentration (30 mM; HG). In these models, all of the mitochondrial respiratory parameters, including basal and maximal respiration, ATP production, and spare respiratory capacity, were significantly decreased. Podocytes that were treated with HG showed a fragmented mitochondrial network, together with a decrease in expression of the mitochondrial fusion markers MEN1, MFN2, and OPA1, and an increase in the activity of the fission marker DRP1. We showed that markers of mitochondrial biogenesis, such as PGC-1 alpha and TFAM, decreased in HG-treated podocytes. Moreover, PINK1/parkin-dependent mitophagy was inhibited in these cells. These results provide evidence that hyperglycemia impairs mitochondrial dynamics and turnover, which may underlie the remarkable deterioration of mitochondrial respiration parameters in glomeruli and podocytes.