1. Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice
- Author
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Mahaba B. Eiwaz, James A. McCormick, Adam C. Munhall, Yoshio Funahashi, Motoko Yanagita, Katsuyuki Matsushita, Turgay Saritas, Michael P. Hutchens, Jessica Hebert, Megan N. Nickerson, and Kiyoshi Mori
- Subjects
Male ,medicine.medical_specialty ,Renal function ,Apoptosis ,Context (language use) ,urologic and male genital diseases ,Rhabdomyolysis ,Blood Urea Nitrogen ,Kidney Tubules, Proximal ,Mice ,Internal medicine ,Animals ,Medicine ,Protease Inhibitors ,Mice, Knockout ,Proteinuria ,Cilastatin ,Myoglobin ,business.industry ,Myoglobinuria ,Acute kidney injury ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Endocytosis ,Disease Models, Animal ,Low Density Lipoprotein Receptor-Related Protein-2 ,Basic Research ,Endocrinology ,Nephrology ,Knockout mouse ,medicine.symptom ,business ,Glomerular Filtration Rate ,Kidney disease ,medicine.drug - Abstract
Background Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of acute kidney injury (AKI) and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate chronic kidney disease (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 glomerular filtration rate (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.
- Published
- 2021