Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, P.R. China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China.
Mol Med Rep. 2018 Jun;17(6):7618-7626. doi: 10.3892/mmr.2018.8809. Epub 2018 Mar 28.
Acute kidney injury (AKI) is one of the most common complications of sepsis. The roles of autophagy in AKI have been demonstrated in previous studies. Sequestosome‑1 (p62) has been demonstrated to serve essential roles in autophagy. The dysregulation of autophagy causes p62 accumulation, which is associated with increased inflammation and tumorigenesis. However, the expression patterns and role of p62 in septic AKI remain unknown. The present study detected the renal autophagy level, and the expression and localization of p62, in a lipopolysaccharide (LPS)‑induced AKI mouse model. The results demonstrated that autophagy was induced in the kidneys of LPS‑treated mice. The mRNA and protein levels of p62 were decreased in whole renal tissue samples and increased in mice treated with LPS. Immunohistochemistry indicated that p62 protein was predominantly expressed in the cytoplasm of proximal tubules under normal conditions and was significantly decreased following LPS injection into the cortex. In addition, p62 protein was gradually redistributed to the outer and inner medullas following treatment with LPS. In vitro experiments demonstrated that overexpression of p62 significantly decreased the viability and increased the lactate dehydrogenase (LDH) release and apoptosis rate, of renal tubular epithelial cells. By contrast, interference with p62 expression using small interfering RNA increased the cell viability and decreased the LDH release and apoptosis rate. The results of the present study demonstrated that p62 may aggravate LPS‑induced acute kidney injury in mice by promoting apoptosis in renal tubular epithelial cells.
急性肾损伤 (AKI) 是脓毒症最常见的并发症之一。先前的研究已经证明自噬在 AKI 中的作用。自噬体蛋白 1 (p62) 已被证明在自噬中发挥重要作用。自噬的失调导致 p62 积累，这与炎症和肿瘤发生的增加有关。然而，p62 在脓毒症性 AKI 中的表达模式和作用尚不清楚。本研究在脂多糖 (LPS) 诱导的 AKI 小鼠模型中检测了肾脏自噬水平以及 p62 的表达和定位。结果表明，自噬在 LPS 处理的小鼠肾脏中被诱导。LPS 处理的小鼠全肾组织样本中 p62 的 mRNA 和蛋白水平降低，而 LPS 处理的小鼠中 p62 增加。免疫组织化学分析表明，p62 蛋白在正常情况下主要表达在近端肾小管的细胞质中，而在 LPS 注射到皮质后则显著减少。此外，p62 蛋白在 LPS 处理后逐渐重新分布到外和内髓质。体外实验表明，p62 的过表达显著降低了肾小管上皮细胞的活力，增加了乳酸脱氢酶 (LDH) 的释放和细胞凋亡率。相反，使用小干扰 RNA 干扰 p62 的表达增加了细胞活力，降低了 LDH 的释放和细胞凋亡率。本研究的结果表明，p62 可能通过促进肾小管上皮细胞凋亡而加重 LPS 诱导的小鼠急性肾损伤。
