Abstract：
Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of AKI acquired in hospital, lacking of effective interventions. In the study, we identified the renal beneficial role of 2, 2-dimethylthiazolidine hydrochloride (DMTD), a safer compound which is readily hydrolyzed to cysteamine, in the rodent model of CI-AKI. Our data showed that administration of DMTD attenuated the impaired renal function and tubular injury induced by the contrast agent. Levels of MDA, 4-hydroxynonenal, ferrous iron and morphological signs showed that contrast agent induced ferroptosis, which could be inhibited in the DMTD group. In vitro, DMTD suppressed ferroptosis induced by ioversol in the cultured tubular cells. Treatment of DMTD upregulated glutathione (GSH) and glutathione peroxidase 4 (GPX4). Moreover, we found that DMTD promoted the ubiquitin-mediated proteasomal degradation of Keap1, and thus increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Mechanistically, increase of the ubiquitylation degradation of Keap1 mediates the upregulated effect of DMTD on Nrf2. Consequently, activated Nrf2/Slc7a11 results in the increase of GSH and GPX4, and therefore leads to the inhibition of ferroptosis. Herein, we imply DMTD as a potential therapeutic agent for the treatment of CI-AKI.
摘要：
对比剂诱导的急性肾损伤(CI-AKI)已成为医院获得性AKI的第三大病因,缺乏有效的干预措施。在研究中,我们确定了2，2-二甲基噻唑烷盐酸盐（DMTD）的肾脏有益作用，一种更安全的化合物，容易水解为半胱胺，在CI-AKI的啮齿动物模型中。我们的数据表明，DMTD的施用减轻了造影剂引起的肾功能受损和肾小管损伤。MDA的水平，4-羟基壬烯醛，亚铁和形态学征象表明造影剂诱导铁凋亡，在DMTD组中可以被抑制。体外，DMTD抑制了培养的肾小管细胞中ioversol诱导的铁凋亡。DMTD上调谷胱甘肽(GSH)和谷胱甘肽过氧化物酶4(GPX4)的处理。此外，我们发现DMTD促进了泛素介导的Keap1的蛋白酶体降解，从而增加了核因子红系2相关因子2（Nrf2）的活性。机械上,Keap1泛素化降解的增加介导DMTD对Nrf2的上调作用。因此,激活的Nrf2/Slc7a11导致GSH和GPX4的增加，因此导致铁凋亡的抑制。在这里，我们认为DMTD是治疗CI-AKI的潜在治疗剂。
