He Kang, Xia Lei, Zhang Jianjun
Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Int Urol Nephrol. 2018 Mar;50(3):571-580. doi: 10.1007/s11255-017-1735-3. Epub 2017 Nov 9.
We have recently reported lipopolysaccharide (LPS) pretreatment attenuated renal ischemia/reperfusion injury (IRI), but the exact mechanism remains to be well elucidated. It was reported that heat shock protein (Hsp) 27 was up-regulated after administration of LPS, but whether a direct link existed between Hsp27 up-regulation and LPS-induced protection against renal IRI is still unknown.
Mice were exposed to IRI or sham procedure, with pretreatment of LPS or not. Quercetin, an inhibitor of Hsp27 synthesis, was used, and an RNA interference with adenovirus vector using short hairpin RNA targeting Hsp27 was developed for inhibition of Hsp27 in mice. In addition, mice trans-infected with adenovirus vector encoding Hsp27 were used to testify the role of Hsp27 overexpression in LPS-induced renoprotection. Renal function, histological damage, inflammatory reaction, oxidative stress and apoptosis indices were measured. Western blot analysis was used to detect expression of Hsp27.
We found LPS pretreatment stimulated renal up-regulation of Hsp27 and reduced renal IRI proven by less renal dysfunction, histological damage, inflammatory reaction, oxidative stress and apoptosis. It was observed that inhibition of Hsp27 synthesis by Quercetin abolished LPS-induced renoprotective effects. After renal knockdown of Hsp27, LPS-induced tolerance against renal IRI was largely removed. Mice with Hsp27 overexpression showed significantly improved renal function after IRI and LPS combined with Hsp27 overexpression had a synergistic effect on protection against renal IRI.
Administration of LPS produces protective effects against renal IRI via Hsp27 up-regulation. Preconditional Hsp27 up-regulation might have a great potential for the treatment of renal IRI via ameliorating apoptosis.
我们最近报道了脂多糖（LPS）预处理可减轻肾缺血/再灌注损伤（IRI），但其确切机制仍有待充分阐明。据报道，LPS给药后热休克蛋白（Hsp）27上调，但Hsp27上调与LPS诱导的肾IRI保护之间是否存在直接联系仍不清楚。
将小鼠暴露于IRI或假手术中，进行或不进行LPS预处理。使用槲皮素（一种Hsp27合成抑制剂），并开发了一种使用靶向Hsp27的短发夹RNA的腺病毒载体RNA干扰技术来抑制小鼠体内的Hsp27。此外，使用转染编码Hsp27的腺病毒载体的小鼠来验证Hsp27过表达在LPS诱导的肾保护中的作用。测量肾功能、组织学损伤、炎症反应、氧化应激和细胞凋亡指标。采用蛋白质免疫印迹分析检测Hsp27的表达。
我们发现LPS预处理可刺激肾脏Hsp27上调，并减轻肾IRI，表现为肾功能障碍、组织学损伤、炎症反应、氧化应激和细胞凋亡减轻。观察到槲皮素抑制Hsp27合成可消除LPS诱导的肾保护作用。在肾脏中敲低Hsp27后，LPS诱导的肾IRI耐受性基本消失。Hsp27过表达的小鼠在IRI后肾功能显著改善，LPS与Hsp27过表达联合使用对肾IRI具有协同保护作用。
LPS给药通过上调Hsp27对肾IRI产生保护作用。预先上调Hsp27可能通过改善细胞凋亡在肾IRI治疗中具有巨大潜力。
