IRCCS Neuromed, Pozzilli, Isernia, Italy.
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy.
Cell Death Dis. 2021 Oct 8;12(10):919. doi: 10.1038/s41419-021-04188-4.
The mitochondrial uncoupling protein 2 (UCP2) plays a protective function in the vascular disease of both animal models and humans. UCP2 downregulation upon high-salt feeding favors vascular dysfunction in knock-out mice, and accelerates cerebrovascular and renal damage in the stroke-prone spontaneously hypertensive rat. Overexpression of UCP2 counteracts the negative effects of high-salt feeding in both animal models. We tested in vitro the ability of UCP2 to stimulate autophagy and mitophagy as a mechanism mediating its protective effects upon high-salt exposure in endothelial and renal tubular cells. UCP2 silencing reduced autophagy and mitophagy, whereas the opposite was true upon UCP2 overexpression. High-salt exposure increased level of reactive oxygen species (ROS), UCP2, autophagy and autophagic flux in both endothelial and renal tubular cells. In contrast, high-salt was unable to induce autophagy and autophagic flux in UCP2-silenced cells, concomitantly with excessive ROS accumulation. The addition of an autophagy inducer, Tat-Beclin 1, rescued the viability of UCP2-silenced cells even when exposed to high-salt. In summary, UCP2 mediated the interaction between high-salt-induced oxidative stress and autophagy to preserve viability of both endothelial and renal tubular cells. In the presence of excessive ROS accumulation (achieved upon UCP2 silencing and high-salt exposure of silenced cells) autophagy was turned off. In this condition, an exogenous autophagy inducer rescued the cellular damage induced by excess ROS level. Our data confirm the protective role of UCP2 toward high-salt-induced vascular and renal injury, and they underscore the role of autophagy/mitophagy as a mechanism counteracting the high-salt-induced oxidative stress damage.
线粒体解偶联蛋白 2（UCP2）在动物模型和人类的血管疾病中发挥保护作用。高盐喂养会导致 UCP2 下调，从而有利于敲除小鼠的血管功能障碍，并加速易卒中型自发性高血压大鼠的脑血管和肾脏损伤。UCP2 的过表达可抵消两种动物模型中高盐喂养的负面影响。我们在体外测试了 UCP2 刺激自噬和线粒体自噬的能力，作为其在高盐暴露时介导保护作用的机制，在内皮细胞和肾小管细胞中。UCP2 沉默减少了自噬和线粒体自噬，而 UCP2 过表达则相反。高盐暴露增加了内皮细胞和肾小管细胞中活性氧（ROS）、UCP2、自噬和自噬通量的水平。相比之下，高盐不能诱导 UCP2 沉默细胞中的自噬和自噬通量，同时伴随着过多的 ROS 积累。添加自噬诱导剂 Tat-Beclin 1 可挽救 UCP2 沉默细胞的活力，即使它们暴露于高盐中。总之，UCP2 介导了高盐诱导的氧化应激与自噬之间的相互作用，以维持内皮细胞和肾小管细胞的活力。在 ROS 过度积累的情况下（通过 UCP2 沉默和沉默细胞暴露于高盐时实现），自噬被关闭。在这种情况下，外源性自噬诱导剂可挽救由过量 ROS 水平引起的细胞损伤。我们的数据证实了 UCP2 对高盐诱导的血管和肾脏损伤的保护作用，并且强调了自噬/线粒体自噬作为一种机制，可抵消高盐诱导的氧化应激损伤。
