UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability.
UCP1 alleviates renal interstitial fibrosis progression through oxidative stress pathway mediated by SIRT3 protein stability.
复制标题
UCP1通过SIRT3蛋白稳定性介导的氧化应激途径促进肾间质纤维化进展
DOI：
10.1186/s12967-023-04376-0
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发表时间：
2023-08-02
影响因子：
7.4
通讯作者：
Zhang, Chun
中科院分区：
文献类型：
--
作者：
Xiong, Wei;Xiong, Zhiyong;Song, Anni;Lei, Chuntao;Ye, Chen;Su, Hua;Zhang, Chun
肾间质纤维化是不同病因慢性肾脏病（CKD）进行性发展的共同途径，是导致终末期肾病的主要病理基础。虽然目前对肾间质纤维化的研究正在逐步深入，但诊断和治疗方法仍十分缺乏。解偶联蛋白1（Uncoupling protein 1，UCP 1）是线粒体内膜上的一种核编码蛋白，在调节能量代谢和线粒体内环境稳定中起重要作用。然而，UCP 1的生物学意义和CKD发展中的潜在调控机制仍不清楚。采用单侧输尿管梗阻（UUO）模型建立肾纤维化动物模型，采用TGF-β1刺激HK 2细胞建立肾纤维化体外模型。Western blot、免疫印迹和免疫组化检测UCP 1的表达。UCP 1被UCP 1过表达慢病毒和UCP 1激动剂CL 316243上调。采用Western blot和免疫荧光法检测上皮间质转化（EMT）相关标志物I型胶原、纤连蛋白、抗氧化酶SOD 2和CAT，活性氧检测试剂盒检测活性氧（ROS）的产生。通过siRNA进行SIRT 3敲低。这项研究表明，UCP 1在肾纤维化和UUO模型患者中显著下调。进一步的研究发现，UCP 1过表达和CL 316243治疗（UCP 1激动剂）逆转了体内和体外肾纤维化模型中的EMT和细胞外基质（ECM）积聚。同时，UCP 1通过增加SIRT 3的稳定性来减少ROS的产生。当SIRT 3被敲低时，ROS的产生减少。上调UCP 1的表达可以通过稳定SIRT 3抑制氧化应激的发生，从而减少EMT和ECM的积累，最终缓解肾间质纤维化。它将为CKD的治疗提供新的指导和靶点。在线版本包含补充材料，可通过10.1186/s12967-023-04376-0获得。
Renal interstitial fibrosis is a common pathway for the progressive development of chronic renal diseases (CKD) with different etiology, and is the main pathological basis leading to end-stage renal disease. Although the current research on renal interstitial fibrosis is gradually deepening, the diagnosis and treatment methods are still very lacking. Uncoupling protein 1 (UCP1) is a nuclear encoded protein in mitochondria inner membrane and plays an important role in regulating energy metabolism and mitochondrial homeostasis. However, the biological significance of UCP1 and potential regulatory mechanisms in the development of CKD remain unclear. Unilateral ureteral obstruction (UUO) model was used to construct the animal model of renal fibrosis, and TGF-β1 stimulation of HK2 cells was used to construct the vitro model of renal fibrosis. UCP1 expression was detected by Western blot, immunoblot analysis and immunohistochemistry. UCP1 was upregulated by UCP1 overexpressing lentivirus and UCP1 agonist CL316243. Western blot and immunofluorescence were used to detect epithelial mesenchymal transition (EMT)-related markers, such as collagen I, fibronectin, antioxidant enzyme SOD2 and CAT. Reactive oxygen species (ROS) production was detected by ROS detection kit. SIRT3 knockdown was performed by siRNA. This study presents that UCP1 is significantly downregulated in patients with renal fibrosis and UUO model. Further studies discover that UCP1 overexpression and CL316243 treatments (UCP1 agonists) reversed EMT and extracellular matrix (ECM) accumulation in renal fibrosis models in vivo and in vitro. Simultaneously, UCP1 reduced the ROS production by increasing the stability of SIRT3. When SIRT3 was knocked down, the production of ROS decreased. Elevating the expression of UCP1 can inhibit the occurrence of oxidative stress by stabilizing SIRT3, thereby reducing EMT and ECM accumulation, and ultimately alleviating renal interstitial fibrosis. It will provide new instructions and targets for the treatment of CKD. The online version contains supplementary material available at 10.1186/s12967-023-04376-0.
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影响因子：
64.8
作者：
Kuppe C;Ibrahim MM;Kranz J;Zhang X;Ziegler S;Perales-Patón J;Jansen J;Reimer KC;Smith JR;Dobie R;Wilson-Kanamori JR;Halder M;Xu Y;Kabgani N;Kaesler N;Klaus M;Gernhold L;Puelles VG;Huber TB;Boor P;Menzel S;Hoogenboezem RM;Bindels EMJ;Steffens J;Floege J;Schneider RK;Saez-Rodriguez J;Henderson NC;Kramann R
通讯作者：
Kramann R
影响因子：
13.5
作者：
Czuba LC;Hillgren KM;Swaan PW
通讯作者：
Swaan PW
DOI：
10.3390/antiox11020322
发表时间：
2022-02-06
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
Hirschenson J;Melgar-Bermudez E;Mailloux RJ
通讯作者：
Mailloux RJ
影响因子：
30.8
作者：
Fleury, C;Neverova, M;Warden, CH
通讯作者：
Warden, CH
影响因子：
4.8
作者：
Kim, Ayoung;Koo, Ja Hyun;Kim, Sang Geon
通讯作者：
Kim, Sang Geon