{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T02:26:27Z","timestamp":1772763987617,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,19]],"date-time":"2020-05-19T00:00:00Z","timestamp":1589846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015R1A1A1A05001599"],"award-info":[{"award-number":["2015R1A1A1A05001599"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Science and ICT, Republic of Korea","award":["2018R1C1B5045006"],"award-info":[{"award-number":["2018R1C1B5045006"]}]},{"DOI":"10.13039\/501100014234","name":"Korean Society of Nephrology","doi-asserted-by":"publisher","award":["Chong Kun Dang, 2016"],"award-info":[{"award-number":["Chong Kun Dang, 2016"]}],"id":[{"id":"10.13039\/501100014234","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002560","name":"Soonchunhyang University","doi-asserted-by":"publisher","award":["Research Fund"],"award-info":[{"award-number":["Research Fund"]}],"id":[{"id":"10.13039\/501100002560","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cilastatin is a specific inhibitor of renal dehydrodipeptidase-1. We investigated whether cilastatin preconditioning attenuates renal ischemia-reperfusion (IR) injury via hypoxia inducible factor-1\u03b1 (HIF-1\u03b1) activation. Human proximal tubular cell line (HK-2) was exposed to ischemia, and male C57BL\/6 mice were subjected to bilateral kidney ischemia and reperfusion. The effects of cilastatin preconditioning were investigated both in vitro and in vivo. In HK-2 cells, cilastatin upregulated HIF-1\u03b1 expression in a time- and dose-dependent manner. Cilastatin enhanced HIF-1\u03b1 translation via the phosphorylation of Akt and mTOR was followed by the upregulation of erythropoietin (EPO) and vascular endothelial growth factor (VEGF). Cilastatin did not affect the expressions of PHD and VHL. However, HIF-1\u03b1 ubiquitination was significantly decreased after cilastatin treatment. Cilastatin prevented the IR-induced cell death. These cilastatin effects were reversed by co-treatment of HIF-1\u03b1 inhibitor or HIF-1\u03b1 small interfering RNA. Similarly, HIF-1\u03b1 expression and its upstream and downstream signaling were significantly enhanced in cilastatin-treated kidney. In mouse kidney with IR injury, cilastatin treatment decreased HIF-1\u03b1 ubiquitination independent of PHD and VHL expression. Serum creatinine level and tubular necrosis, and apoptosis were reduced in cilastatin-treated kidney with IR injury, and co-treatment of cilastatin with an HIF-1\u03b1 inhibitor reversed these effects. Thus, cilastatin preconditioning attenuated renal IR injury via HIF-1\u03b1 activation.<\/jats:p>","DOI":"10.3390\/ijms21103583","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T02:48:24Z","timestamp":1589942904000},"page":"3583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cilastatin Preconditioning Attenuates Renal Ischemia-Reperfusion Injury via Hypoxia Inducible Factor-1\u03b1 Activation"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7856-4955","authenticated-orcid":false,"given":"Yu Ah","family":"Hong","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"So Young","family":"Jung","sequence":"additional","affiliation":[{"name":"Clinical Research Institute, Daejeon St. Mary\u2018s Hospital, Daejeon 34943, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keum Jin","family":"Yang","sequence":"additional","affiliation":[{"name":"Clinical Research Institute, Daejeon St. Mary\u2018s Hospital, Daejeon 34943, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dai Sig","family":"Im","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Natural Sciences, Soonchunhyang University, Asan 31538, Korea"},{"name":"SH Company, 507, SCH BIT Business Incubator B\/D, 22 Soonchunhyang-ro, Shinchang, Asan, Chungnam 31538, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyung Hwan","family":"Jeong","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheol Whee","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyeon Seok","family":"Hwang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/ki.1996.380","article-title":"Epidemiology of acute renal failure: A prospective, multicenter, community-based study. 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