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Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice
Journal of the American Society of Nephrology ( IF 10.3 ) Pub Date : 2021-10-01 , DOI: 10.1681/asn.2020030263
Katsuyuki Matsushita 1 , Kiyoshi Mori 2 , Turgay Saritas 3, 4 , Mahaba B Eiwaz 1 , Yoshio Funahashi 1 , Megan N Nickerson 1 , Jessica F Hebert 1 , Adam C Munhall 1 , James A McCormick 3 , Motoko Yanagita 5, 6 , Michael P Hutchens 1, 7
Affiliation  

Background

Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of AKI and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate CKD. Development of specific pharmacologic therapy is desirable because supportive care is nearly impossible in austere environments. Myoglobin, the principal cause of rhabdomyolysis-related AKI, undergoes megalin-mediated endocytosis in proximal tubule cells, a process that specifically injures these cells.

Methods

To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL/6 mice and mice (14–32 weeks old) with proximal tubule–specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation.

Results

Inducible proximal tubule–specific deletion of megalin was highly protective in this mouse model of rhabdomyolysis-induced AKI. The megalin knockout mice demonstrated preserved GFR, reduced proximal tubule injury (as indicated by kidney injury molecule-1), and reduced renal apoptosis 24 hours after injury. These effects were accompanied by increased urinary myoglobin clearance. Unlike littermate controls, the megalin-deficient mice also did not develop progressive GFR decline and persistent new proteinuria. Administration of the pharmacologic megalin inhibitor cilastatin to wild-type mice recapitulated the renoprotective effects of megalin deletion. This cilastatin-mediated renoprotective effect was dependent on megalin. Cilastatin administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by megalin deletion.

Conclusions

We conclude that megalin plays a critical role in rhabdomyolysis-induced AKI, and megalin interference and inhibition ameliorate rhabdomyolysis-induced AKI. Further investigation of megalin inhibition may inform translational investigation of a novel potential therapy.



中文翻译:

西司他丁改善横纹肌溶解诱导的小鼠 AKI

背景

横纹肌溶解是骨骼肌的破坏,是自然灾害和武装冲突背景下 AKI 和死亡的重要原因。横纹肌溶解也可能引发 CKD。开发特定的药物治疗是可取的,因为在严峻的环境中几乎不可能进行支持性护理。肌红蛋白是横纹肌溶解相关 AKI 的主要原因,它在近端小管细胞中经历巨蛋白介导的内吞作用,该过程专门损伤这些细胞。

方法

为了研究巨蛋白是否在横纹肌溶解诱导的 AKI 小鼠模型中具有保护作用,我们使用了雄性 C57BL/6 小鼠和具有近端小管特异性巨蛋白缺失的小鼠(14-32 周龄)。我们使用了一个充分表征的横纹肌溶解模型,在生理盐水中注射 50% 的甘油,然后进行禁水​​。

结果

在横纹肌溶解诱导的 AKI 小鼠模型中,可诱导的近端小管特异性巨蛋白缺失具有高度保护作用。巨蛋白敲除小鼠表现出保留的 GFR、减少的近端小管损伤(如肾损伤分子-1 所示)以及损伤后 24 小时的肾细胞凋亡减少。这些影响伴随着尿肌红蛋白清除率的增加。与同窝对照不同,缺乏巨蛋白的小鼠也没有出现进行性 GFR 下降和持续性新蛋白尿。对野生型小鼠施用药理学巨蛋白抑制剂西司他丁可重现巨蛋白缺失的肾脏保护作用。这种西司他丁介导的肾脏保护作用依赖于巨蛋白。

结论

我们得出结论,巨蛋白在横纹肌溶解诱导的 AKI 中起关键作用,巨蛋白干扰和抑制可改善横纹肌溶解诱导的 AKI。对巨蛋白抑制的进一步研究可能会为新型潜在疗法的转化研究提供信息。

更新日期:2021-10-02
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