Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease

Am J Physiol Renal Physiol. 2016 Nov 1;311(5):F877-F889. doi: 10.1152/ajprenal.00089.2016. Epub 2016 Jul 20.

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.

Keywords: adenine; anemia; chronic kidney disease; growth delay; hepcidin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine
  • Anemia / diagnostic imaging
  • Anemia / genetics
  • Anemia / metabolism*
  • Animals
  • Disease Models, Animal
  • Femur / diagnostic imaging
  • Growth Disorders / chemically induced
  • Growth Disorders / genetics
  • Growth Disorders / metabolism*
  • Growth Plate / diagnostic imaging
  • Hepcidins / genetics
  • Hepcidins / metabolism*
  • Mice
  • Mice, Knockout
  • Renal Insufficiency, Chronic / chemically induced
  • Renal Insufficiency, Chronic / diagnostic imaging
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism*
  • X-Ray Microtomography

Substances

  • Hepcidins
  • Adenine