SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis.
SIRT3 Deficiency Sensitizes Angiotensin-II-Induced Renal Fibrosis.
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作者：
Feng X;Su H;He X;Chen JX;Zeng H
研究背景：SIRT 3在心血管疾病中起重要作用。我们先前的研究表明，SIRT 3敲除（SIRT 3 KO）促进心脏周细胞-成纤维细胞转化。在这项研究中，我们调查了周细胞和铁参与血管紧张素II（Ang-II）介导的SIRT 3 KO小鼠肾纤维化。方法和结果：NG 2-DsRed小鼠和NG 2-DsRed-SIRT 3敲除（SIRT 3 KO）小鼠输注生理盐水或Ang-II（1000 ng/kg/min）4周。检测肾纤维化程度、铁含量和活性氧（ROS）水平。Masson三色染色显示SIRT 3 KO增强Ang-II诱导的肾纤维化。免疫组化显示Ang-II处理增加了肾脏中NG 2-DsRed+细胞的数量，SIRT 3 KO进一步增强了NG 2-DsRed+细胞。此外，SIRT 3 KO促进周细胞分化为成纤维细胞，如通过NG 2-DsRed/FSP-1共染色所证明的。此外，在Ang-II输注后，SIRT 3 KO使DsRed/FSP-1+和DsRed/转化生长因子-β1（TGF-β1）+成纤维细胞升高。SIRT 3 KO小鼠中Ang-II诱导的I型胶原和TGF-β1表达也增强。SIRT 3 KO显著加重Ang-II诱导的铁积累。这伴随着乙酰-p53、HO-1和FPN表达的增加。此外，SIRT 3 KO敏化Ang-II诱导的p47 phox和gp 91 phox上调以及肾脏中ROS形成增加。结论：我们的研究表明，SIRT 3缺乏敏化Ang-II诱导的肾纤维化的机制涉及促进周细胞分化成纤维细胞，加剧铁过载和加速NADPH氧化酶衍生的ROS形成。
Background: Sirtuin 3 (SIRT3) has a crucial role in the cardiovascular diseases. Our previous study revealed that SIRT3 knockout (SIRT3KO) promoted cardiac pericyte–fibroblast transition. In this study, we investigated the involvement of pericyte and iron in angiotensin II (Ang-II)-mediated renal fibrosis in the SIRT3KO mice. Methods and Results: NG2-DsRed mice and NG2-DsRed-SIRT3 knockout (SIRT3KO) mice were infused with saline or Ang-II (1000 ng/kg/min) for 4 weeks. Renal fibrosis, iron content and reactive oxygen species (ROS) were measured. Masson’s trichrome staining showed that SIRT3KO enhanced Ang-II-induced renal fibrosis. Immunostaining showed that Ang-II treatment increased the number of NG2-DsRed+ cells in the kidney, and SIRT3KO further enhanced NG2-DsRed+ cells. Moreover, SIRT3KO promoted pericyte differentiation into fibroblasts as evidenced by co-staining NG2-DsRed/FSP-1. Furthermore, DsRed/FSP-1+ and DsRed/transforming growth factor-β1 (TGF-β1)+ fibroblasts were elevated by SIRT3KO after Ang-II infusion. Ang-II-induced collagen I and TGF-β1 expression was also enhanced in the SIRT3KO mice. SIRT3KO significantly exacerbated Ang-II-induced iron accumulation. This was accompanied by an increase in acetyl-p53, HO-1 and FPN expression. Further, SIRT3KO sensitized Ang-II-induced upregulation of p47phox and gp91phox together with increased ROS formation in the kidney. Conclusion: Our study suggests that SIRT3 deficiency sensitized Ang-II-induced renal fibrosis by the mechanisms involved in promoting differentiation of pericytes into fibroblasts, exacerbating iron overload and accelerating NADPH oxidase-derived ROS formation.
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影响因子：
5.5
作者：
Han, Wei-Qing;Xu, Lian;Gao, Ping-Jin
通讯作者：
Gao, Ping-Jin
影响因子：
3.5
作者：
He X;Zeng H;Roman RJ;Chen JX
通讯作者：
Chen JX
影响因子：
5
作者：
Siddesha, Jalahalli M.;Valente, Anthony J.;Sakamuri, Siva S. V. P.;Yoshida, Tadashi;Gardner, Jason D.;Somanna, Naveen;Takahashi, Chiaki;Noda, Makoto;Chandrasekar, Bysani
通讯作者：
Chandrasekar, Bysani
DOI：
10.1161/hypertensionaha.113.01837
发表时间：
2013-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Xia Y;Entman ML;Wang Y
通讯作者：
Wang Y
DOI：
10.1161/hypertensionaha.118.11144
发表时间：
2018-07
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Chuaiphichai S;Rashbrook VS;Hale AB;Trelfa L;Patel J;McNeill E;Lygate CA;Channon KM;Douglas G
通讯作者：
Douglas G