{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:47:27Z","timestamp":1791002847189,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["R01 DK098141"],"award-info":[{"award-number":["R01 DK098141"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DFG German Research Foundation","award":["332853055"],"award-info":[{"award-number":["332853055"]}]},{"name":"Else Kr\u00f6ner-Fresenius Stiftung","award":["2015_A197"],"award-info":[{"award-number":["2015_A197"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["19gm1210009"],"award-info":[{"award-number":["19gm1210009"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP19gm5010002"],"award-info":[{"award-number":["JP19gm5010002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP19gm0610011"],"award-info":[{"award-number":["JP19gm0610011"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"United States Department of Defense","doi-asserted-by":"crossref","award":["W81XWH2010196"],"award-info":[{"award-number":["W81XWH2010196"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development","award":["1I01BX004288"],"award-info":[{"award-number":["1I01BX004288"]}]},{"name":"Portland Veterans Affairs Medical Center."}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["JASN"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n                    <jats:title>Significance Statement<\/jats:title>\n                    <jats:p>Rhabdomyolysis causes severe AKI and death in settings such as earthquakes and armed conflict. Specific treatment is not available and care is difficult to provide in these austere environments. Skeletal muscle myoglobin is a renal toxin that causes AKI in this syndrome. Proximal tubular megalin participates in myoglobin endocytosis and may be an AKI mediator. The authors demonstrate in a mouse model that proximal tubular megalin plays a critical role in rhabdomyolysis-induced AKI. In this model, proximal tubule\u2013specific megalin deletion ameliorated AKI, and this effect was recapitulated by administration of cilastatin, a megalin inhibitor. This translational study thus identifies megalin as a mediator of rhabdomyolysis-induced AKI and suggests a novel mechanism by which it may be possible to ameliorate this condition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL\/6 mice and mice (14\u201332 weeks old) with proximal tubule\u2013specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Inducible proximal tubule\u2013specific 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1681\/asn.2020030263","type":"journal-article","created":{"date-parts":[[2021,8,2]],"date-time":"2021-08-02T14:00:17Z","timestamp":1627912817000},"page":"2579-2594","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":62,"title":["Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice"],"prefix":"10.1681","volume":"32","author":[{"given":"Katsuyuki","family":"Matsushita","sequence":"first","affiliation":[{"name":"Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, Oregon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7285-8351","authenticated-orcid":false,"given":"Kiyoshi","family":"Mori","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, 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