SLC22 Transporters in the Fly Renal System Regulate Response to Oxidative Stress In Vivo.
SLC22 Transporters in the Fly Renal System Regulate Response to Oxidative Stress In Vivo.
复制标题
蝇肾脏系统中的SLC22转运蛋白调节体内对氧化应激的反应。
DOI：
10.3390/ijms222413407
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发表时间：
2021-12-14
影响因子：
5.6
通讯作者：
Nigam SK
中科院分区：
文献类型：
--
作者：
Zhang P;Azad P;Engelhart DC;Haddad GG;Nigam SK
人类肾脏和其他组织中的几种 SLC22 转运蛋白被认为可以调节内源性小抗氧化分子，例如尿酸、麦角硫因、肉碱和肉碱衍生物。这些转运蛋白包括有机阴离子转运蛋白 (OAT)、OCTN/OCTN 相关转运蛋白和有机阳离子转运蛋白 (OCT) 亚组。在哺乳动物中，很难显示这些转运蛋白在氧化应激期间的明确体内作用。相关果蝇 SLC22 的普遍敲低——包括与我们之前在哺乳动物中发现的转运蛋白同源的转运蛋白，例如“类蝇转运蛋白”FLIPT1 (SLC22A15) 和 FLIPT2 (SLC22A16)——已显示出针对氧化应激的适度保护作用。然而，这些果蝇转运蛋白往往被广泛表达，并且尚不清楚是否存在它们的表达至关重要的器官。使用两种组织选择性敲低策略，与之前的全果蝇敲低以及亲本和WT品系相比，我们能够证明对氧化应激的更大和更长久的保护（CG6126：p < 0.001，CG4630：p < 0.01，CG16727：p < 0.0001和CG6006：p < 0.01）。马氏小管和其他可能的组织（例如肠道、脂肪体、神经系统）中的表达对于控制氧化应激似乎至关重要。这四个果蝇SLC22基因与人类SLC22转运蛋白相似（CG6126：SLC22A16、CG16727：SLC22A7、CG4630：SLC22A3和CG6006：SLC22A1、SLC22A2、SLC22A3、SLC22A6、SLC22A7、SLC22A8， SLC22A11、SLC22A12 (URAT1)、SLC22A13、SLC22A14)——其中许多在肾脏中高表达。与遥感和信号传导理论一致，这表明果蝇肾脏系统内多个 SLC22 转运蛋白在体内氧化应激反应中发挥重要作用，可能是通过与非肾组织中的 SLC22 对应物相互作用。我们还注意到，许多人类亲属都是著名的药物转运者。我们的工作不仅表明了 SLC22 转运蛋白在果蝇肾系统中的重要性，而且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.
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影响因子：
4.3
作者：
Apidianakis Y;Rahme LG
通讯作者：
Rahme LG
影响因子：
4.3
作者：
Ali, Sohrab N.;Dayarathna, Thamara K.;Leong, Hon S.
通讯作者：
Leong, Hon S.
影响因子：
5.6
作者：
Engelhart, Darcy C.;Azad, Priti;Nigam, Sanjay K.
通讯作者：
Nigam, Sanjay K.
影响因子：
4.8
作者：
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通讯作者：
Endou, H
DOI：
10.26355/eurrev_202006_21542
发表时间：
2020-06-01
影响因子：
3.3
作者：
Fan, Q-X;Gong, S-Q;Zhang, F-J
通讯作者：
Zhang, F-J