Nox4 is a Target for Tuberin Deficiency Syndrome.
Nox4 is a Target for Tuberin Deficiency Syndrome.
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Nox4 是马铃薯球蛋白缺乏综合症的靶标。
DOI：
10.1038/s41598-018-21838-4
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发表时间：
2018
影响因子：
4.6
通讯作者：
Abboud,HannaE
中科院分区：
文献类型：
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作者：
Shi,Qian;Viswanadhapalli,Suryavathi;Friedrichs,WilliamE;Velagapudi,Chakradhar;Szyndralewiez,Cédric;Bansal,Shweta;Bhat,ManzoorA;Choudhury,GoutamGhosh;Abboud,HannaE
TSC2 失活或缺陷导致结节性硬化症 (TSC) 病理的机制尚不完全清楚。我们发现 TSC 患者的肾血管平滑肌脂肪瘤和 Tsc2+/- 小鼠的肾皮质表现出活性氧 (ROS) 水平升高。肾近端肾小管上皮细胞中马铃薯蛋白（由 TSC2 基因编码的蛋白质）的下调显着增加了 ROS，同时增强了 Nox4。同样，我们发现 Tsc2+/- 小鼠肾皮质和 TSC 患者肾血管平滑肌脂肪瘤中 Nox4 水平升高。马铃薯蛋白缺乏与 mTORC1 的激活有关。雷帕霉素、靶向 raptor 的 shRNA 或抑制 S6 激酶显着抑制 Nox4 的表达，导致马铃薯蛋白下调的近端肾小管上皮细胞中 ROS 的产生减弱。相反，mTORC1 的激活增加了 Nox4 和 ROS。这些结果表明 Nox4 可能是马铃薯球蛋白缺乏引起的疾病的潜在靶标。使用裸鼠马铃薯蛋白无效肾小管细胞的异种移植模型，反义Nox4和Nox1/4的特异性抑制剂GKT137831均显着抑制肿瘤生长。因此，我们的结果表明，马铃薯球蛋白和 Nox4 之间存在拮抗关系，可驱动马铃薯球蛋白缺乏综合征中的肿瘤发生，并将 Nox4 确定为开发 TSC 疗法的靶点。
The mechanism by whichTSC2inactivation or deficiency contributes to the pathology of tuberous sclerosis complex (TSC) is not fully clear. We show that renal angiomyolipomas from TSC patients and kidney cortex fromTsc2+/− mice exhibit elevated levels of reactive oxygen species (ROS). Downregulation of tuberin (protein encoded byTSC2gene) in renal proximal tubular epithelial cells significantly increased ROS concomitant with enhanced Nox4. Similarly, we found elevated levels of Nox4 in the renal cortex ofTsc2+/− mice and in the renal angiomyolipomas from TSC patients. Tuberin deficiency is associated with activation of mTORC1. Rapamycin, shRNAs targeting raptor, or inhibition of S6 kinase significantly inhibited the expression of Nox4, resulting in attenuation of production of ROS in tuberin-downregulated proximal tubular epithelial cells. In contrast, activation of mTORC1 increased Nox4 and ROS. These results indicate that Nox4 may be a potential target for tuberin-deficiency-derived diseases. Using a xenograft model from tuberin-null tubular cells in nude mice, both anti-sense Nox4 and GKT137831, a specific inhibitor of Nox1/4, significantly inhibited the tumor growth. Thus, our results demonstrate the presence of an antagonistic relationship between tuberin and Nox4 to drive oncogenesis in the tuberin deficiency syndrome and identify Nox4 as a target to develop a therapy for TSC.