Grdović Nevena, Rajić Jovana, Arambašić Jovanović Jelena, Dinić Svetlana, Tolić Anja, Đorđević Miloš, Đorđević Marija, Trifunović Svetlana, Vidaković Melita, Uskoković Aleksandra, Mihailović Mirjana
Department of Molecular Biology, Institute for Biological Research "Siniša Stanković, " National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
Department of Cytology, Institute for Biological Research "Siniša Stanković, " National Institute of Republic of Serbia, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia.
Oxid Med Cell Longev. 2021 Mar 11;2021:6669352. doi: 10.1155/2021/6669352. eCollection 2021.
-Lipoic acid (ALA) is widely used as a nutritional supplement and therapeutic agent in diabetes management. Well-established antioxidant and hypoglycemic effects of ALA were considered to be particularly important in combating diabetic complications including renal injury. The present study evaluated the potential of ALA to affect profibrotic events in kidney that could alter its structure and functioning. ALA was administered intraperitoneally (10 mg/kg) to nondiabetic and streptozotocin-induced diabetic male Wistar rats for 4 and 8 weeks. The effects of ALA were assessed starting from structural/morphological alterations through changes that characterize profibrotic processes, to regulation of collagen gene expression in kidney. Here, we demonstrated that ALA improved systemic glucose and urea level, reduced formation of renal advanced glycation end products (AGEs), and maintained renal structural integrity in diabetic rats. However, profibrotic events provoked in diabetes were not alleviated by ALA since collagen synthesis/deposition and expression of transforming growth factor-1 (TGF-1) and -smooth muscle actin (-SMA) remained elevated in ALA-treated diabetic rats, especially after 8 weeks of diabetes onset. Moreover, 8 weeks treatment of nondiabetic rats with ALA led to the development of profibrotic features reflected in increased collagen synthesis/deposition. Besides the TGF-1 downstream signaling, the additional mechanism underlying the upregulation of collagen IV in nondiabetic rats treated with ALA involves decreased DNA methylation of its promoter that could arise from increased Tet1 expression. These findings emphasize the therapeutic caution in the use of ALA, especially in patients with renal diabetic complication.
硫辛酸（ALA）作为一种营养补充剂和治疗药物，在糖尿病管理中被广泛应用。ALA已被证实的抗氧化和降血糖作用在对抗包括肾损伤在内的糖尿病并发症方面被认为尤为重要。本研究评估了ALA对肾脏中可能改变其结构和功能的促纤维化事件的影响。将ALA以腹腔注射的方式（10毫克/千克）给予非糖尿病和链脲佐菌素诱导的糖尿病雄性Wistar大鼠，持续4周和8周。从结构/形态学改变开始，通过促纤维化过程的特征变化，到肾脏中胶原蛋白基因表达的调节，评估ALA的作用效果。在此，我们证明了ALA改善了糖尿病大鼠的全身血糖和尿素水平，减少了肾脏晚期糖基化终产物（AGEs）的形成，并维持了肾脏结构的完整性。然而，糖尿病引发的促纤维化事件并未被ALA缓解，因为在接受ALA治疗的糖尿病大鼠中，胶原蛋白合成/沉积以及转化生长因子-1（TGF-1）和α-平滑肌肌动蛋白（α-SMA）的表达仍然升高，尤其是在糖尿病发病8周后。此外，用ALA对非糖尿病大鼠进行8周治疗导致了促纤维化特征的出现，表现为胶原蛋白合成/沉积增加。除了TGF-1下游信号通路外，ALA处理的非糖尿病大鼠中IV型胶原蛋白上调的另一个潜在机制涉及到其启动子DNA甲基化的减少，这可能是由于Tet1表达增加所致。这些发现强调了在使用ALA时需谨慎治疗，尤其是在患有糖尿病肾病并发症的患者中。
