کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
10814930 1058433 2014 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Smad3/Nox4-mediated mitochondrial dysfunction plays a crucial role in puromycin aminonucleoside-induced podocyte damage
چکیده انگلیسی
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 mitochondrial dysfunction in a puromycin aminonucleoside (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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 26, Issue 12, December 2014, Pages 2979-2991
نویسندگان
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