{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T05:27:34Z","timestamp":1754112454862,"version":"3.37.3"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Renibus Therapeutics"},{"name":"Southlake"},{"DOI":"10.13039\/100005895","name":"Fred Hutchinson Cancer Research Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005895","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Iron sucrose (FeS) administration induces a state of renal preconditioning, protecting against selected forms of acute kidney injury (AKI). Recent evidence suggests that recombinant hepcidin also mitigates acute renal damage. Hence the goals of this study were to determine whether a new proprietary FeS formulation (\u2018RBT-3\u2019) can acutely activate the hepcidin (HAMP1) gene in humans, raising plasma and renal hepcidin concentrations; assess whether the kidney participates in this posited RBT-3\u2013hepcidin generation response; test whether RBT-3 can mitigate a clinically relevant AKI model (experimental cisplatin toxicity) and explore whether mechanisms in addition to hepcidin generation are operative in RBT-3\u2019s cytoprotective effects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Healthy human volunteers (n = 9) and subjects with Stages 3\u20134 CKD (n = 9) received 120, 240 or 360\u2009mg of RBT-3 (intravenously over 2\u2009h). Plasma and urine samples were collected and assayed for hepcidin levels (0\u201372\u2009h post-RBT-3 injection). In complementary mouse experiments, RBT-3 effects on hepatic versus renal hepcidin (HAMP1) messenger RNA (mRNA) and protein levels were compared. RBT-3\u2019s impact on the mouse Nrf2 pathway and on experimental cisplatin nephrotoxicity was assessed. Direct effects of exogenous hepcidin on in vivo and in vitro (HK-2 cells) cisplatin toxicity were also tested.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>RBT-3 induced rapid, dose-dependent and comparable plasma hepcidin increases in both healthy volunteers and chronic kidney disease subjects (\u223c15 times baseline within 24\u2009h). Human kidney hepcidin exposure was confirmed by 4-fold urinary hepcidin increases. RBT-3 up-regulated mouse hepcidin mRNA, but much more so in kidney (&amp;gt;25 times) versus liver (\u223c2 times). RBT-3 also activated kidney Nrf2 [increased Nrf2 nuclear binding; increased Nrf2-responsive gene mRNAs: heme oxygenase-1, sulfiredoxin-1, glutamate-cysteine ligase catalytic subunit and NAD(P)H quinone dehydrogenase 1]. RBT-3 preconditioning (18\u2009h time lapse) markedly attenuated experimental cisplatin nephrotoxicity (\u223c50% blood urea nitrogen\/creatinine decrements), in part by reducing renal cisplatin uptake by 40%. Exogenous hepcidin (without RBT-3) treatment conferred protection against mild in vivo (but not in vitro) cisplatin toxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>RBT-3 acutely and dramatically up-regulates cytoprotective hepcidin production, increasing renal hepcidin levels. However, additional cytoprotective mechanisms are activated by RBT-3 (e.g. Nrf2 activation; reduced cisplatin uptake). Thus RBT-3-induced preconditioning likely confers renal resistance to cisplatin via an interplay of multiple cytoprotective activities.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ndt\/gfaa348","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T20:25:29Z","timestamp":1606767929000},"page":"465-474","source":"Crossref","is-referenced-by-count":7,"title":["Iron sucrose (\u2018RBT-3\u2019) activates the hepatic and renal <i>HAMP1<\/i> gene, evoking renal hepcidin loading and resistance to cisplatin nephrotoxicity"],"prefix":"10.1093","volume":"36","author":[{"given":"Richard A","family":"Zager","sequence":"first","affiliation":[{"name":"Department of Medicine, The University of Washington, Seattle, WA, USA"},{"name":"Fred Hutchinson Cancer Research Center, Seattle, WA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali C M","family":"Johnson","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Research Center, Seattle, WA, USA"},{"name":"Renibus Therapeutics, Southlake, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renibus","family":"Therapeutics","sequence":"additional","affiliation":[{"name":"Renibus Therapeutics, Southlake, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"2021022208581752900_gfaa348-B1","doi-asserted-by":"crossref","first-page":"12727","DOI":"10.1074\/jbc.R117.781823","article-title":"Iron homeostasis: an anthropocentric perspective","volume":"292","author":"Coffey","year":"2017","journal-title":"J Biol Chem"},{"key":"2021022208581752900_gfaa348-B2","doi-asserted-by":"crossref","first-page":"e1004998","DOI":"10.1371\/journal.ppat.1004998","article-title":"Hepcidin and host defense against infectious diseases","volume":"11","author":"Michels","year":"2015","journal-title":"PLoS 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