title: Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease.
abstract: Growth delay is common in children with chronic kidney disease (CKD), often associated with poor quality of life. The role of anemia in uremic growth delay is poorly understood. Here we describe an induction of uremic growth retardation by a 0.2% adenine diet in wild-type (WT) and hepcidin gene (Hamp) knockout (KO) mice, compared with their respective littermates fed a regular diet. Experiments were started at weaning (3 wk). After 8 wk, blood was collected and mice were euthanized. Adenine-fed WT mice developed CKD (blood urea nitrogen 82.8 ± 11.6 mg/dl and creatinine 0.57 ± 0.07 mg/dl) and were 2.1 cm shorter compared with WT controls. WT adenine-fed mice were anemic and had low serum iron, elevated Hamp, and elevated IL6 and TNF-α. WT adenine-fed mice had advanced mineral bone disease (serum phosphorus 16.9 ± 3.1 mg/dl and FGF23 204.0 ± 115.0 ng/ml) with loss of cortical and trabecular bone volume seen on microcomputed tomography. Hamp disruption rescued the anemia phenotype resulting in improved growth rate in mice with CKD, thus providing direct experimental evidence of the relationship between Hamp pathway and growth impairment in CKD. Hamp disruption ameliorated CKD-induced growth hormone-insulin-like growth factor 1 axis derangements and growth plate alterations. Disruption of Hamp did not mitigate the development of uremia, inflammation, and mineral and bone disease in this model. Taken together, these results indicate that an adenine diet can be successfully used to study growth in mice with CKD. Hepcidin appears to be related to pathways of growth retardation in CKD suggesting that investigation of hepcidin-lowering therapies in juvenile CKD is warranted.
authors.affiliation: Weill Cornell Medicine, New York, New York; oma9005@med.cornell.edu.
authors.forename: Oleh
authors.initials: O
authors.lastname: Akchurin
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Angara
authors.initials: A
authors.lastname: Sureshbabu
authors.affiliation: Hospital for Special Surgery, New York, New York; and.
authors.forename: Steve B
authors.initials: SB
authors.lastname: Doty
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Yuan-Shan
authors.initials: YS
authors.lastname: Zhu
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Edwin
authors.initials: E
authors.lastname: Patino
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Susanna
authors.initials: S
authors.lastname: Cunningham-Rundles
authors.affiliation: Weill Cornell Medicine, New York, New York.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Choi
authors.affiliation: Weill Cornell Medicine, New York, New York.|Hospital for Special Surgery, New York, New York; and.
authors.forename: Adele
authors.initials: A
authors.lastname: Boskey
authors.affiliation: Weill Cornell Medicine, New York, New York.|Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
mesh_terms: D000225:Adenine; D000740:Anemia / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005269:Femur / Q000000981:diagnostic imaging; D000089703:Fibroblast Growth Factor-23; D006130:Growth Disorders / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D006132:Growth Plate / Q000000981:diagnostic imaging; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: C000717428:Fgf23 protein, mouse; D064451:Hepcidins; D000089703:Fibroblast Growth Factor-23; D000225:Adenine
keywords: adenine; anemia; chronic kidney disease; growth delay; hepcidin