Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, C49
Does gastrin play a role in haematopoiesis?
S. Kovac1, G. J. Anderson2, W. S. Alexander3, A. Shulkes1, G. Baldwin1
1. Surgery, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia. 2. Queensland Institute of Medical Research, Brisbane, Queensland, Australia. 3. Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Introduction: Gastrins are peptide hormones important for gastric acid secretion and growth of the gastrointestinal mucosa. We have previously demonstrated that ferric ions bind to gastrins, that the gastrin-ferric ion complex interacts with the iron transport protein transferrin in vitro, and that circulating gastrin concentrations positively correlate with transferrin saturation in vivo. These observations formed the basis for our proposal that circulating gastrins may act as chaperones for the uptake of ferric ions by apo-transferrin (1). Aim: To investigate the effects of long-term dietary iron deficiency in mice with altered circulating gastrin concentrations. Methods: Gastrin-deficient (Gas-/-) and hypergastrinemic cholecystokinin receptor 2-deficient (Cck2r-/-) mice, both of which have reduced basal gastric acid secretion, were fed diets containing normal, low or high iron (160, 3 or 6000 mg of iron per kg wet weight, respectively). After 6 weeks, mice were anaesthetised by i.p. injection with ketamine (100 mg/kg)/xylazine (10 mg/kg), blood was collected by cardiac puncture, and iron status was assessed by measurement of serum ferritin and hepatic iron concentrations. Circulating concentrations of erythropoietin and thrombopoietin were measured by ELISA assay. Expression of hepatic Hamp mRNA, of duodenal Dmt-1 and Fpn-1 mRNA, and of duodenal ferroportin and DMT-1 protein, was quantitated by real-time PCR and by Western blotting, respectively. Results: Iron homeostasis in both strains appeared normal until the animals were challenged by iron deficiency, when only the Gas-/- mice developed severe anaemia. In iron-deficient Gas-/- mice, massive (3-fold) splenomegaly was apparent together with an increased number of splenic megakaryocytes accompanied by thrombocytosis. Furthermore, a significant increase in erythropoietin concentration (16-fold) was observed in the Gas-/- mice compared to the wild-type Balb/c mice on the low iron diet. The expression of the mRNA encoding the iron regulatory peptide hepcidin, Hamp, was down-regulated in both Cck2r-/- and Gas-/- mice on a low iron diet, but interestingly the reduction was greater in Cck2r-/- mice and smaller in Gas-/- mice than in the corresponding wild-type strains. The changes in Hamp mRNA expression were also reflected in Fpn-1 and Dmt-1 mRNA and protein concentrations. In the iron-deficient Cck2r-/- mice the concentration of Fpn-1 mRNA was 1.9-fold lower than in the wild-type mice on the same diet. Conclusion: These data suggest that gastrins play an important direct role, unrelated to their ability to stimulate acid secretion, in haematopoiesis under conditions of iron deficiency.
Where applicable, experiments conform with Society ethical requirements