Improved mitochondrial function underlies the protective effect of pirfenidone against tubulointerstitial fibrosis in 5/6 nephrectomized rats.
Improved mitochondrial function underlies the protective effect of pirfenidone against tubulointerstitial fibrosis in 5/6 nephrectomized rats.
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改善线粒体功能是吡非尼酮对 5/6 肾切除大鼠肾小管间质纤维化的保护作用的基础
DOI：
10.1371/journal.pone.0083593
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu BC
中科院分区：
文献类型：
--
作者：
Chen JF;Liu H;Ni HF;Lv LL;Zhang MH;Zhang AH;Tang RN;Chen PS;Liu BC
功能障碍的线粒体参与慢性肾病（CKD）的进展。吡非尼酮是一种新发现的抗纤维化药物。然而，其机制仍不清楚。线粒体功能障碍是发生在肾纤维化发作之前的早期事件。在此背景下，我们研究了吡非尼酮对线粒体的保护作用及其与肾近端小管细胞凋亡和氧化应激的相关性。建立大鼠残肾模型。进一步在体外研究使用鱼藤酮（线粒体呼吸链复合物I抑制剂）的人肾近端肾小管上皮细胞（HK 2），以检查吡非尼酮的线粒体保护作用。吡非尼酮通过稳定线粒体膜电位、维持ATP产生和改善线粒体DNA（mtDNA）拷贝数来保护线粒体结构和功能。吡非尼酮通过抑制线粒体凋亡信号通路减少肾小管细胞凋亡。吡非尼酮还通过增强锰超氧化物歧化酶（Mn-SOD）和抑制细胞内活性氧（ROS）的产生来降低氧化应激，这表明抗氧化作用至少部分通过线粒体途径发生。吡非尼酮可能在肾纤维化发作前有效，因为该药物通过保护肾近端小管细胞中的线粒体发挥其抗纤维化作用。
Dysfunctional mitochondria participate in the progression of chronic kidney disease (CKD). Pirfenidone is a newly identified anti-fibrotic drug. However, its mechanism remains unclear. Mitochondrial dysfunction is an early event that occurs prior to the onset of renal fibrosis. In this context, we investigated the protective effect of pirfenidone on mitochondria and its relevance to apoptosis and oxidative stress in renal proximal tubular cells. A remnant kidney rat model was established. Human renal proximal tubular epithelial cells (HK2) using rotenone, a mitochondrial respiratory chain complex Ι inhibitor were further investigated in vitro to examine the mitochondrial protective effect of pirfenidone. Pirfenidone protected mitochondrial structures and functions by stabilizing the mitochondrial membrane potential, maintaining ATP production and improving the mitochondrial DNA (mtDNA) copy number. Pirfenidone decreased tubular cell apoptosis by inhibiting the mitochondrial apoptotic signaling pathway. Pirfenidone also reduced oxidative stress by enhancing manganese superoxide dismutase (Mn-SOD) and inhibiting intracellular reactive oxygen species (ROS) generation, which suggested that the anti-oxidant effects occurred at least partially via the mitochondrial pathway. Pirfenidone may be effective prior to the onset of renal fibrosis because this drug exerts its anti-fibrotic effect by protection of mitochondria in renal proximal tubular cells.
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DOI：
10.1073/pnas.1302764110
发表时间：
2013-08-13
影响因子：
11.1
作者：
Manoli, Irini;Sysol, Justin R.;Venditti, Charles P.
通讯作者：
Venditti, Charles P.
影响因子：
19.6
作者：
通讯作者：
--
DOI：
10.1186/1755-1536-3-16
发表时间：
2010-09-01
期刊：
Fibrogenesis & tissue repair
影响因子：
--
作者：
Macías-Barragán J;Sandoval-Rodríguez A;Navarro-Partida J;Armendáriz-Borunda J
通讯作者：
Armendáriz-Borunda J
影响因子：
168.9
作者：
Noble, Paul W.;Albera, Carlo;du Bois, Roland M.
通讯作者：
du Bois, Roland M.
影响因子：
13.6
作者：
Sharma, Kumar;Ix, Joachim H.;Kopp, Jeffrey B.
通讯作者：
Kopp, Jeffrey B.