A single approach to targeting transferrin receptor 2 corrects iron and erythropoietic defects in murine models of anemia of inflammation and chronic kidney disease

• Verfasst von: Olivari, Violante [VerfasserIn]
• Verfasst von: Di Modica, Simona Maria [VerfasserIn]
• Verfasst von: Lidonnici, Maria Rosa [VerfasserIn]
• Verfasst von: Aghajan, Mariam [VerfasserIn]
• Verfasst von: Cordero-Sanchez, Celia [VerfasserIn]
• Verfasst von: Tanzi, Emanuele [VerfasserIn]
• Verfasst von: Pettinato, Mariateresa [VerfasserIn]
• Verfasst von: Pagani, Alessia [VerfasserIn]
• Verfasst von: Tiboni, Francesca [VerfasserIn]
• Verfasst von: Silvestri, Laura [VerfasserIn]
• Verfasst von: Guo, Shuling [VerfasserIn]
• Verfasst von: Ferrari, Giuliana [VerfasserIn]
• Verfasst von: Nai, Antonella [VerfasserIn]
• Titel: A single approach to targeting transferrin receptor 2 corrects iron and erythropoietic defects in murine models of anemia of inflammation and chronic kidney disease
• Verf.angabe: Violante Olivari, Simona Maria Di Modica, Maria Rosa Lidonnici, Mariam Aghajan, Celia Cordero-Sanchez, Emanuele Tanzi, Mariateresa Pettinato, Alessia Pagani, Francesca Tiboni, Laura Silvestri, Shuling Guo, Giuliana Ferrari and Antonella Nai
• E-Jahr: 2023
• Jahr: July 2023
• Umfang: 13 S.
• Fussnoten: Online verfügbar: 27. März 2023, Artikelversion: 20. Juni 2023 ; Gesehen am 22.08.2023
• Titel Quelle: Enthalten in: Kidney international
• Ort Quelle: New York, NY : Elsevier, 1972
• Jahr Quelle: 2023
• Band/Heft Quelle: 104(2023), 1 vom: Juli, Seite 61-73
• ISSN Quelle: 1523-1755
• DOI: doi:10.1016/j.kint.2023.03.012
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: anemia
• Sach-SW: chronic kidney disease
• Sach-SW: inflammation
• K10plus-PPN: 1857230310

Abstract

Anemia is a common complication of systemic inflammation. Proinflammatory cytokines both decrease erythroblast sensitivity to erythropoietin (EPO) and increase the levels of the hepatic hormone hepcidin, sequestering iron in stores and causing functional iron deficiency. Anemia of chronic kidney disease (CKD) is a peculiar form of anemia of inflammation, characterized by impaired EPO production paralleling progressive kidney damage. Traditional therapy based on increased EPO (often in combination with iron) may have off-target effects due to EPO interaction with its non-erythroid receptors. Transferrin Receptor 2 (Tfr2) is a mediator of the iron-erythropoiesis crosstalk. Its deletion in the liver hampers hepcidin production, increasing iron absorption, whereas its deletion in the hematopoietic compartment increases erythroid EPO sensitivity and red blood cell production. Here, we show that selective hematopoietic Tfr2 deletion ameliorates anemia in mice with sterile inflammation in the presence of normal kidney function, promoting EPO responsiveness and erythropoiesis without increasing serum EPO levels. In mice with CKD, characterized by absolute rather than functional iron deficiency, Tfr2 hematopoietic deletion had a similar effect on erythropoiesis but anemia improvement was transient because of limited iron availability. Also, increasing iron levels by downregulating only hepatic Tfr2 had a minor effect on anemia. However, simultaneous deletion of hematopoietic and hepatic Tfr2, stimulating erythropoiesis and increased iron supply, was sufficient to ameliorate anemia for the entire protocol. Thus, our results suggest that combined targeting of hematopoietic and hepatic Tfr2 may be a therapeutic option to balance erythropoiesis stimulation and iron increase, without affecting EPO levels.