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Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage
Yu, Lixia1; Liu, Yanbo2; Wu, Yanfeng3; Liu, Qifeng1; Feng, Jianhua1; Gu, Xiaoxia1; Xiong, Yan1; Fan, Qingfeng4,5; Ye, Jianming1
关键词Puromycin aminonucleoside (PA) Podocyte damage Mitochondrial dysfunction Smad3 NADPH oxidative (Nox4) Proteinuria
刊名CELLULAR SIGNALLING
2014-12-01
DOI10.1016/j.cellsig.2014.08.030
26期:12页:2979-2991
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Cell Biology
研究领域[WOS]Cell Biology
关键词[WOS]GROWTH-FACTOR-BETA ; HIGH GLUCOSE ; TGF-BETA ; DIABETIC-NEPHROPATHY ; GLOMERULAR-DISEASES ; PROTECTS PODOCYTES ; OXIDATIVE STRESS ; NADPH OXIDASES ; IN-VITRO ; APOPTOSIS
英文摘要

Podocyte depletion due to apoptosis is the key hallmark of proteinuric kidney disease progression. Recently, several studies reported that mitochondrial (mt) dysfunction is involved in podocyte injury, while the underlying molecular mechanisms remain elusive. This study investigated the potential proximal signaling related to in vitro and in vivo mitochondria( dysfunction in a puromycin aminonudeoside (PA)-induced podocyte injury model. PA time- and dose-dependently resulted in cultured mouse podocyte damage, presenting with an increase of apoptotic cells and induction of activated caspase3/9. PA also caused mitochondrial damage and dysfunction based on the downregulation of the mtDNA level, decrease of transcriptional factors mtTfa and Nrf-1, decrease of CoxI, II and IV, and reduction of the oxygen consumption level and mitochondrial membrane potential level as well as excessive production of cellular ROS. Additionally, antioxidant MnSOD and catalase levels were decreased in mitochondrial fractions, and reduction of complex I and IV activity was also observed in PA-stimulated podocytes. Furthermore, an obvious translocation of p-Smad3 from the cytosol to nuclei and induction of mitochondrial Nox4 were detected following PA application. The PA-induced shift of cytochrome c was observed from mitochondria to the cytoplasm. Induction of Nox4 by PA administration was significantly repressed by Smad3-shRNA, while Nox4-shRNA showed no effect on PA-induced p-Smad3 activation. Notably, both Smad3 and Nox4 silencing significantly prevented the reduction of the mtDNA level, restored mitochondrial function, and decreased cellular apoptosis in PA-stimulated podocytes. A similar mitochondrial dysfunction was obtained in a PA-injected nephropathy rat, which was effectively inhibited by treatment with the antiproteinuric drug prednisone. In addition, Dab2 knockdown decreased albumin uptake and influx whereas it showed no effect on cellular apoptosis in PA-stimulated podocytes. In conclusion, our findings demonstrated that Smad3-Nox4 axis-mediated mitochondrial dysfunction is involved in PA-induced podocyte damage likely via increasing ROS generation and activating the cytochrome c-caspase9-caspase3 apoptotic signaling pathway. Dab2 may be required for the increased permeability of podocytes following injury. (C) 2014 Elsevier Inc. All rights reserved.

语种英语
WOS记录号WOS:000345107700043
项目编号81300577 ; 30801250
资助机构National Natural Science Foundation of China ; Science and Technology Foundation of First People&prime ; s Hospital of Kunshan ; Key Specialty Funds of Suzhou
引用统计
被引频次:15[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/67598
专题北京大学第一临床医学院_儿科
作者单位1.Jiangsu Univ, Affiliated Kunshan Hosp, Peoples Hosp Kunshan 1, Dept Nephrol, Kunshan 215300, Jiangsu, Peoples R China
2.Jilin Univ, Hosp 1, Dept Pediat, Changchun 130031, Peoples R China
3.Jilin Univ, Hosp 2, Dept Pneumol, Changchun 130031, Peoples R China
4.Univ Penn, Renal Electrolyte & Hypertens Div, Perelman Sch Med, Philadelphia, PA 19104 USA
5.Peking Univ, Dept Pediat, Hosp 1, Beijing 100034, Peoples R China
推荐引用方式
GB/T 7714
Yu, Lixia,Liu, Yanbo,Wu, Yanfeng,et al. Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage[J]. CELLULAR SIGNALLING,2014,26(12):2979-2991.
APA Yu, Lixia.,Liu, Yanbo.,Wu, Yanfeng.,Liu, Qifeng.,Feng, Jianhua.,...&Ye, Jianming.(2014).Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage.CELLULAR SIGNALLING,26(12),2979-2991.
MLA Yu, Lixia,et al."Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage".CELLULAR SIGNALLING 26.12(2014):2979-2991.
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