人类肾脏和其他组织中的几种SLC22转运蛋白被认为调节内源性小抗氧化分子,如尿酸,麦角硫酮,肉碱,和肉碱衍生物。这些转运蛋白包括来自有机阴离子转运蛋白(OAT)的转运蛋白,OCTN/OCTN相关,和有机阳离子转运蛋白(OCT)亚组。在哺乳动物中,在氧化应激过程中,很难明确显示这些转运蛋白在体内的作用。相关果蝇SLC22的普遍敲除-包括与我们先前在哺乳动物中鉴定出的那些同源的转运蛋白,例如“类蝇推定转运蛋白”FLIPT1(SLC22A15)和FLIPT2(SLC22A16)-已显示出适度的抗氧化应激保护作用。然而,这些苍蝇运输者倾向于广泛表达,目前还不清楚是否有一个器官,其中他们的表达是关键的。使用两种组织选择性敲除策略,与以前的全蝇敲除以及亲本和WT菌株相比,我们能够证明对氧化应激的保护作用更大,更长(CG6126:p<0.001,CG4630:p<0.01,CG16727:p<0.0001和CG6006:p<0.01)。在Malpighian小管和可能的其他组织中的表达(例如,gut,gut脂肪的身体,神经系统)对于管理氧化应激至关重要。这四个果蝇SLC22基因与人类SLC22转运蛋白(CG6126:SLC22A16,CG16727:SLC22A7,CG4630:SLC22A3和CG6006:SLC22A1,SLC22A2,SLC22A3,SLC22A6,SLC22A7,SLC22A8,SLC22A11(SLURA12)相似SLC22A13,SLC22A14)-其中许多在肾脏中高度表达。与遥感和信号理论相一致,这表明在果蝇肾脏系统内多个SLC22转运蛋白的氧化应激反应中具有重要的体内作用,也许是通过与非肾组织中SLC22对应物的相互作用。我们还注意到,许多人类亲属是众所周知的药物转运蛋白。我们的工作不仅表明了SLC22转运蛋白在蝇肾系统中的重要性,而且还通过检查它们在哺乳动物氧化应激和器官串扰中的作用为体内研究奠定了基础。
Several SLC22 transporters in the human kidney and other tissues are thought to regulate endogenous small antioxidant molecules such as uric acid, ergothioneine, carnitine, and carnitine derivatives. These transporters include those from the organic anion transporter (OAT), OCTN/OCTN-related, and organic cation transporter (OCT) subgroups. In mammals, it has been difficult to show a clear in vivo role for these transporters during oxidative stress. Ubiquitous knockdowns of related Drosophila SLC22s-including transporters homologous to those previously identified by us in mammals such as the \"Fly-Like Putative Transporters\" FLIPT1 (SLC22A15) and FLIPT2 (SLC22A16)-have shown modest protection against oxidative stress. However, these fly transporters tend to be broadly expressed, and it is unclear if there is an organ in which their expression is critical. Using two tissue-selective knockdown strategies, we were able to demonstrate much greater and longer protection from oxidative stress compared to previous whole fly knockdowns as well as both parent and WT strains (CG6126: p < 0.001, CG4630: p < 0.01, CG16727: p < 0.0001 and CG6006: p < 0.01). Expression in the Malpighian tubule and likely other tissues as well (e.g., gut, fat body, nervous system) appear critical for managing oxidative stress. These four Drosophila SLC22 genes are similar to human SLC22 transporters (CG6126: SLC22A16, CG16727: SLC22A7, CG4630: SLC22A3, and CG6006: SLC22A1, SLC22A2, SLC22A3, SLC22A6, SLC22A7, SLC22A8, SLC22A11, SLC22A12 (URAT1), SLC22A13, SLC22A14)-many of which are highly expressed in the kidney. Consistent with the Remote Sensing and Signaling Theory, this indicates an important in vivo role in the oxidative stress response for multiple SLC22 transporters within the fly renal system, perhaps through interaction with SLC22 counterparts in non-renal tissues. We also note that many of the human relatives are well-known drug transporters. Our work not only indicates the importance of SLC22 transporters in the fly renal system but also sets the stage for in vivo studies by examining their role in mammalian oxidative stress and organ crosstalk.