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 MFN1, MFN2, and OPA1, and an increase in the activity of the fission marker DRP1. We showed that markers of mitochondrial biogenesis, such as PGC-1α 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.

足细胞构成肾小球滤过屏障的外层。它们的能量需求很大程度上取决于有效的氧化呼吸，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，并导致糖尿病肾病的发生。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类足细胞中，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 产量和备用呼吸能力，均显着下降。用 HG 处理的足细胞显示出破碎的线粒体网络，以及线粒体融合标记物 MFN1、MFN2 和 OPA1 的表达减少，以及裂变标记物 DRP1 的活性增加。我们发现，在 HG 处理的足细胞中，线粒体生物发生的标记物（例如 PGC-1α 和 TFAM）减少。此外，PINK1/parkin 依赖性线粒体自噬在这些细胞中受到抑制。这些结果提供了证据，表明高血糖会损害线粒体动力学和周转，这可能是肾小球和足细胞中线粒体呼吸参数显着恶化的基础。