Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice
Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice
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DOI：
10.1681/asn.2020030263
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发表时间：
2021-10-01
影响因子：
13.6
通讯作者：
Hutchens, Michael P.
中科院分区：
文献类型：
--
作者：
Matsushita, Katsuyuki;Mori, Kiyoshi;Hutchens, Michael P.
背景横纹肌溶解症是骨骼肌的破坏，是自然灾害和武装冲突背景下阿基和死亡的重要原因。横纹肌溶解症也可能引发CKD。开发特定的药物治疗是可取的，因为支持性治疗在严峻的环境中几乎是不可能的。肌红蛋白，横纹肌溶解相关的阿基的主要原因，经历巨蛋白介导的内吞作用在近端小管cells，一个过程，专门伤害这些cells.Methods调查是否巨蛋白是保护性的横纹肌溶解诱导的阿基的小鼠模型，我们使用雄性C57 BL/6小鼠和小鼠（14-32周龄）与近端小管特异性缺失的巨蛋白。我们使用了一个良好的特点横纹肌溶解模型，注射50%甘油在生理盐水之前，水deprivation.Results诱导近端小管特异性缺失的巨蛋白是高度保护在这个小鼠模型横纹肌溶解诱导阿基。巨蛋白敲除小鼠在损伤后24小时表现出保留的GFR、减少的近端小管损伤（如肾损伤分子-1所示）和减少的肾细胞凋亡。这些作用伴随着尿肌红蛋白清除率增加。与同窝对照组不同，megalin缺陷小鼠也没有发生进行性GFR下降和持续的新蛋白尿。对野生型小鼠给予药理学巨蛋白抑制剂西司他丁，重现了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megalin。西司他丁给药引起选择性蛋白尿和抑制肾小管肌红蛋白摄取所造成的megalin deletion.Conclusions相似，我们得出结论，megalin在横纹肌溶解诱导的阿基中起着关键作用，megalin干扰和抑制改善横纹肌溶解诱导的阿基。对巨蛋白抑制的进一步研究可能为新的潜在治疗的翻译研究提供信息。
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.