Mild intracellular acidification by dexamethasone attenuates mitochondrial dysfunction in a human inflammatory proximal tubule epithelial cell model.
Mild intracellular acidification by dexamethasone attenuates mitochondrial dysfunction in a human inflammatory proximal tubule epithelial cell model.
复制标题
DOI：
10.1038/s41598-017-10483-y
复制
发表时间：
2017-09-06
影响因子：
4.6
通讯作者：
Russel FGM
中科院分区：
文献类型：
--
作者：
Schirris TJJ;Jansen J;Mihajlovic M;van den Heuvel LP;Masereeuw R;Russel FGM
脓毒性急性肾损伤（阿基）与生存率低有关，通常需要肾脏替代治疗。糖皮质激素可能通过刺激线粒体功能对脓毒症患者的肾脏产生保护作用。因此，我们研究了地塞米松在实验性炎症近曲小管上皮细胞模型中的线粒体效应。用脂多糖（LPS）处理人近端小管上皮细胞与内毒素血症期间的病理生理过程非常相似，并且导致细胞因子排泄率和细胞活性氧水平增加，以及线粒体膜电位和呼吸能力降低。这些作用被地塞米松减弱。地塞米松特异性地增加线粒体复合物V（CV）的表达和活性，这不能用线粒体质量的增加来解释。最后，我们证明地塞米松酸化细胞内环境，从而逆转LPS诱导的碱化，导致线粒体功能的恢复。这种酸化也为CV表达的增加提供了解释，预期这将补偿酸化环境对该复合物的抑制作用。除了对地塞米松在肾细胞炎症过程中的有益作用的机制见解外，我们的工作还支持线粒体在这一过程中的关键作用，因此为治疗阿基提供了新的治疗途径。
Septic acute kidney injury (AKI) associates with poor survival rates and often requires renal replacement therapy. Glucocorticoids may pose renal protective effects in sepsis via stimulation of mitochondrial function. Therefore, we studied the mitochondrial effects of dexamethasone in an experimental inflammatory proximal tubule epithelial cell model. Treatment of human proximal tubule epithelial cells with lipopolysaccharide (LPS) closely resembles pathophysiological processes during endotoxaemia, and led to increased cytokine excretion rates and cellular reactive oxygen species levels, combined with a reduced mitochondrial membrane potential and respiratory capacity. These effects were attenuated by dexamethasone. Dexamethasone specifically increased the expression and activity of mitochondrial complex V (CV), which could not be explained by an increase in mitochondrial mass. Finally, we demonstrated that dexamethasone acidified the intracellular milieu and consequently reversed LPS-induced alkalisation, leading to restoration of the mitochondrial function. This acidification also provides an explanation for the increase in CV expression, which is expected to compensate for the inhibitory effect of the acidified environment on this complex. Besides the mechanistic insights into the beneficial effects of dexamethasone during renal cellular inflammation, our work also supports a key role for mitochondria in this process and, hence, provides novel therapeutic avenues for the treatment of AKI.
登录
查看更多内容
人参二醇皂苷和地塞米松改善脂多糖诱导的急性肾损伤小鼠模型的肾功能
影响因子：
3.7
作者：
Chen Y;Du Y;Li Y;Wang X;Gao P;Yang G;Fang Y;Meng Y;Zhao X
通讯作者：
Zhao X
影响因子：
13.6
作者：
Kaushal, Gur P.;Shah, Sudhir V.
通讯作者：
Shah, Sudhir V.
影响因子：
3.8
作者：
Kim, Misun;Kim, Jinsun;Song, Eunsook
通讯作者：
Song, Eunsook
影响因子：
7.1
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan
通讯作者：
Auwerx, Johan
影响因子：
19.6
作者：
Ali, R;Amlal, H;Soleimani, M
通讯作者：
Soleimani, M