Department of Nephrology, The Second Hospital of Jilin University, Changchun, China.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine at Baltimore, Baltimore, Maryland, USA.
Biosci Rep. 2020 Sep 30;40(9). doi: 10.1042/BSR20192397.
Endotoxemia-induced acute kidney injury (AKI) is a common clinical condition that lacks effective treatments. Elabela (ELA) is a recently discovered kidney peptide hormone, encoded by the gene apela, and has been reported to improve cardio-renal outcomes in sepsis. However, ELA is a small peptide and is largely unsuitable for clinical use because of its short in vivo half-life. In the present study, we evaluated the potential renoprotective effects of a long-acting constant fragment (Fc)-ELA fusion protein in liposaccharide (LPS)-induced AKI in mice. LPS administration in mice for 5 days greatly lowered the gene expression of apela and impaired kidney function, as evidenced by elevated serum creatinine and the ratio of urine protein to creatinine. In addition, renal inflammation and macrophage infiltration were apparent in LPS-challenged mice. Treatment with the Fc-ELA fusion protein partially restored apela expression and attenuated the kidney inflammation. Moreover, LPS treatment induced reactive oxygen species (ROS) production and apoptosis in kidney HK-2 cells as well as in the mouse kidney, which were mitigated by ELA or Fc-ELA treatment. Finally, we found that ELA promoted the survival of HK-2 cells treated with LPS, and this action was abolished by LY204002, a PI3K/Akt inhibitor. Collectively, we have demonstrated that the Fc-ELA fusion protein has significant renoprotective activities against LPS-induced AKI in mice.
内毒素血症诱导的急性肾损伤（AKI）是一种常见的临床病症，目前缺乏有效的治疗方法。Elabela（ELA）是一种新发现的肾脏肽类激素，由 apela 基因编码，据报道可改善脓毒症的心肾结局。然而，ELA 是一种小肽，由于其体内半衰期短，在很大程度上不适合临床应用。本研究评估了长效恒定片段（Fc）-ELA 融合蛋白在脂多糖（LPS）诱导的 AKI 小鼠模型中的潜在肾脏保护作用。LPS 处理小鼠 5 天可显著降低 apela 的基因表达并损害肾功能，表现为血清肌酐升高和尿蛋白与肌酐比值升高。此外，LPS 处理的小鼠中出现明显的肾脏炎症和巨噬细胞浸润。Fc-ELA 融合蛋白治疗部分恢复了 apela 的表达并减轻了肾脏炎症。此外，LPS 处理诱导 HK-2 细胞和小鼠肾脏中活性氧（ROS）产生和细胞凋亡，而 ELA 或 Fc-ELA 治疗可减轻这些作用。最后，我们发现 ELA 可促进 LPS 处理的 HK-2 细胞的存活，而这种作用可被 PI3K/Akt 抑制剂 LY204002 所阻断。综上，我们证明了 Fc-ELA 融合蛋白对 LPS 诱导的 AKI 小鼠具有显著的肾脏保护作用。
