Laboratory of Molecular and Cellular Nephrology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Wita Stwosza St. 63, 80-308, Gdansk, Poland.
Department of Molecular Biotechnology, Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
J Mol Med (Berl). 2022 Jun;100(6):903-915. doi: 10.1007/s00109-022-02204-4. Epub 2022 May 9.
Alterations of insulin signaling in diabetes are associated with podocyte injury, proteinuria, and renal failure. Insulin stimulates glucose transport to cells and regulates other intracellular processes that are linked to cellular bioenergetics, such as autophagy, gluconeogenesis, fatty acid metabolism, and mitochondrial homeostasis. The dysfunction of mitochondrial dynamics, including mitochondrial fusion, fission, and mitophagy, has been observed in high glucose-treated podocytes and renal cells from patients with diabetes. Previous studies showed that prolonged hyperglycemia is associated with the development of insulin resistance in podocytes, and high glucose-treated podocytes exhibit an increase in mitochondrial fission and decrease in markers of mitophagy. In the present study, we found that deficiency of the main mitophagy protein PTEN-induced kinase 1 (PINK1) significantly increased albumin permeability and hampered glucose uptake to podocytes. We suggest that PINK1 inhibition impairs the insulin signaling pathway, in which lower levels of phosphorylated Akt and membrane fractions of the insulin receptor and glucose transporter-4 were observed. Moreover, PINK1-depleted podocytes exhibited lower podocin and nephrin expression, thus identifying a potential mechanism whereby albumin leakage increases under hyperglycemic conditions when mitophagy is inhibited. In conclusion, we found that PINK1 plays an essential role in insulin signaling and the maintenance of proper permeability in podocytes. Therefore, PINK1 may be a potential therapeutic target for the treatment or prevention of diabetic nephropathy.
胰岛素信号转导在糖尿病中的改变与足细胞损伤、蛋白尿和肾衰竭有关。胰岛素刺激葡萄糖向细胞内转运，并调节与细胞能量代谢相关的其他细胞内过程，如自噬、糖异生、脂肪酸代谢和线粒体稳态。在高糖处理的足细胞和糖尿病患者的肾细胞中观察到线粒体动力学的功能障碍，包括线粒体融合、裂变和自噬。先前的研究表明，长期高血糖与足细胞胰岛素抵抗的发展有关，高糖处理的足细胞表现出线粒体裂变增加和自噬标志物减少。在本研究中，我们发现主要自噬蛋白 PTEN 诱导激酶 1（PINK1）的缺乏显著增加了白蛋白通透性，并阻碍了葡萄糖摄取到足细胞。我们认为 PINK1 抑制会损害胰岛素信号通路，其中观察到磷酸化 Akt 和胰岛素受体和葡萄糖转运蛋白-4 的膜部分的水平降低。此外，耗尽 PINK1 的足细胞表现出 podocin 和 nephrin 表达降低，从而确定了一种潜在的机制，即在自噬被抑制时，高糖条件下白蛋白渗漏增加。总之，我们发现 PINK1 在胰岛素信号转导和维持足细胞的适当通透性方面发挥着重要作用。因此，PINK1 可能是治疗或预防糖尿病肾病的潜在治疗靶点。
