Mazzeo Aurora, Barutta Federica, Bellucci Linda, Trento Marina, Gruden Gabriella, Porta Massimo, Beltramo Elena
Department of Medical Sciences, University of Torino, 10126 Torino, Italy.
Department of Molecular Biotechnology and Health Sciences, University of Torino, 10125 Torino, Italy.
Biomedicines. 2021 Apr 5;9(4):385. doi: 10.3390/biomedicines9040385.
Thiamine helps transketolase in removing toxic metabolites, counteracting high glucose-induced damage in microvascular cells, and progression of diabetic retinopathy/nephropathy in diabetic animals. Diabetic subjects show reduced thiamine levels. Hyperglycemia and reduced thiamine availability concur in impairing thiamine transport inside the blood-retinal barrier, with thiamine transporter-2 (THTR2) primarily involved. Here, we examined the behavior of thiamine transporter-1 (THTR1), THTR2, and their transcription factor Sp1 in response to high glucose and altered thiamine availability in renal cells involved in diabetic nephropathy. Human proximal tubule epithelial cells, podocytes, glomerular endothelial, and mesangial cells were exposed to high glucose and/or thiamine deficiency/oversupplementation. Localization and modulation of THTR1, THTR2, and Sp1; intracellular thiamine; transketolase activity; and permeability to thiamine were examined. Reduced thiamine availability and hyperglycemia impaired thiamine transport and THTR2/Sp1 expression. Intracellular thiamine, transketolase activity, and permeability were strongly dependent on thiamine concentrations and, partly, excess glucose. Glomerular endothelial cells were the most affected by the microenvironmental conditions. Our results confirmed the primary role of THTR2 in altered thiamine transport in cells involved in diabetic microvascular complications. Lack of thiamine concurs with hyperglycemia in impairing thiamine transport. Thiamine supplementation could represent a therapeutic option to prevent or slow the progression of these complications.
硫胺素有助于转酮醇酶清除有毒代谢产物，对抗高糖诱导的微血管细胞损伤，并阻止糖尿病动物发生糖尿病视网膜病变/肾病。糖尿病患者体内硫胺素水平降低。高血糖和硫胺素可用性降低共同损害血视网膜屏障内的硫胺素转运，其中硫胺素转运体-2（THTR2）起主要作用。在此，我们研究了硫胺素转运体-1（THTR1）、THTR2及其转录因子Sp1在糖尿病肾病相关肾细胞中对高糖和硫胺素可用性改变的反应。将人近端肾小管上皮细胞、足细胞、肾小球内皮细胞和系膜细胞暴露于高糖和/或硫胺素缺乏/过量补充环境中。检测THTR1、THTR2和Sp1的定位与调节、细胞内硫胺素、转酮醇酶活性以及硫胺素通透性。硫胺素可用性降低和高血糖会损害硫胺素转运以及THTR2/Sp1表达。细胞内硫胺素、转酮醇酶活性和通透性强烈依赖于硫胺素浓度，部分还依赖于过量葡萄糖。肾小球内皮细胞受微环境条件影响最大。我们的结果证实了THTR2在糖尿病微血管并发症相关细胞中硫胺素转运改变方面的主要作用。硫胺素缺乏与高血糖共同损害硫胺素转运。补充硫胺素可能是预防或延缓这些并发症进展的一种治疗选择。
