Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation

Eur J Pharmacol. 2019 Jan 15;843:113-120. doi: 10.1016/j.ejphar.2018.11.023. Epub 2018 Nov 17.

Abstract

Chronic inflammatory diseases are often associated with anemia. In such conditions, anemia is generally treated with erythropoiesis stimulating agents (ESAs) which are associated with potentially hazardous side effects and poor outcomes. Suboptimal erythropoiesis in chronic inflammation is believed to be caused by elevated hepcidin levels, which causes blockade of iron in tissue stores. In the current work using rodent models of inflammation, an orally available small molecule prolyl hydroxylase inhibitor desidustat was assessed as an effective treatment of anemia of inflammation. In BALB/c mice, a single dose treatment of desidustat attenuated the effect of lipopolysaccharide (LPS) - or turpentine oil-induced inflammation and increased serum erythropoietin (EPO), iron, and reticulocyte count, and decreased serum hepcidin levels. In turpentine oil-induced anemia in BALB/c mice, repeated dose desidustat treatment increased hemoglobin, RBC and hematocrit in a dose related manner. In female Lewis rats, treatment with desidustat markedly reduced PGPS-induced anemia and increased hemoglobin, red blood cell (RBC) and white blood cell (WBC) count, hematocrit, serum iron and spleen iron. These effects of desidustat were associated with reduction in hepcidin (HAMP) expression as well as reduction in serum hepcidin, and increased EPO expression in liver and kidneys. Desidustat treatment caused a significant increase in expression of Duodenal cytochrome B (DcytB), ferroportin (FPN1) and divalent metal transporter 1 (DMT1) in duodenum, and FPN1 and monocyte chemoattractant protein-1 (MCP-1) in liver suggesting an overall influence on iron metabolism. Thus, pharmacological inhibition of prolyl hydroxylase enzymes can be useful in treatment of anemia of inflammation.

Keywords: Anemia of inflammation; Desidustat; Hepcidin; Iron.

MeSH terms

  • Anemia / drug therapy*
  • Anemia / etiology
  • Anemia / metabolism
  • Animals
  • Down-Regulation
  • Erythropoiesis / drug effects*
  • Erythropoietin / blood
  • Female
  • Hepcidins / blood
  • Hepcidins / genetics
  • Inflammation / complications
  • Iron / metabolism
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice, Inbred BALB C
  • Prolyl-Hydroxylase Inhibitors / pharmacology
  • Prolyl-Hydroxylase Inhibitors / therapeutic use*
  • Quinolones / pharmacology
  • Quinolones / therapeutic use*
  • Rats, Inbred Lew
  • Reticulocyte Count

Substances

  • Hepcidins
  • Prolyl-Hydroxylase Inhibitors
  • Quinolones
  • Erythropoietin
  • Iron
  • desidustat