PDF(Pubmed)
Abstract：
Diabetic nephropathy (DN) is a serious microvascular complication of diabetes. Ferroptosis, a new form of cell death, plays a crucial role in the pathogenesis of DN. Renal tubular injury triggered by ferroptosis might be essential in this process. Numerous studies demonstrate that the vitamin D receptor (VDR) exerts beneficial effects by suppressing ferroptosis. However, the underlying mechanism has not been fully elucidated. Thus, they verified the nephroprotective effect of VDR activation and explored the mechanism by which VDR activation suppressed ferroptosis in db/db mice and high glucose-cultured proximal tubular epithelial cells (PTECs). Paricalcitol (PAR) is a VDR agonist that can mitigate kidney injury and prevent renal dysfunction. PAR treatment could inhibit ferroptosis of PTECs through decreasing iron content, increasing glutathione (GSH) levels, reducing malondialdehyde (MDA) generation, decreasing the expression of positive ferroptosis mediator transferrin receptor 1 (TFR-1), and enhancing the expression of negative ferroptosis mediators including ferritin heavy chain (FTH-1), glutathione peroxidase 4 (GPX4), and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11). Mechanistically, VDR activation upregulated the NFE2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway to suppress ferroptosis in PTECs. These findings suggested that VDR activation inhibited ferroptosis of PTECs in DN via modulating the Nrf2/HO-1 signaling pathway.
摘要：
糖尿病肾病(DN)是糖尿病的严重微血管并发症。Ferroptosis,一种新形式的细胞死亡，在DN的发病机制中起着至关重要的作用。铁性凋亡引发的肾小管损伤可能是该过程中必不可少的。大量研究表明，维生素D受体（VDR）通过抑制铁凋亡发挥有益作用。然而,潜在的机制尚未完全阐明。因此，他们验证了VDR激活的肾保护作用,并探讨了VDR激活抑制db/db小鼠和高糖培养的近端肾小管上皮细胞(PTEC)铁凋亡的机制.帕立骨化醇（PAR）是一种VDR激动剂，可以减轻肾脏损伤并预防肾功能障碍。PAR处理可以通过降低铁含量来抑制PTEC的铁凋亡，增加谷胱甘肽（GSH）水平，减少丙二醛（MDA）的产生，降低转铁蛋白受体1（TFR-1）的表达，并增强包括铁蛋白重链（FTH-1）在内的负铁凋亡介质的表达，谷胱甘肽过氧化物酶4（GPX4），和胱氨酸/谷氨酸反转运溶质载体家族7成员11(SLC7A11)。机械上,VDR激活上调NFE2相关因子2/血红素加氧酶-1(Nrf2/HO-1)信号通路以抑制PTEC中的铁凋亡。这些发现表明，VDR激活通过调节Nrf2/HO-1信号通路抑制了DN中PTEC的铁凋亡。
