Prolyl hydroxylase inhibition corrects functional iron deficiency and inflammation-induced anaemia in rats.

Abstract

BACKGROUND AND PURPOSE:

Small-molecule inhibitors of prolyl hydroxylase (PHD) enzymes are a novel target for the treatment of anaemia and functional iron deficiency (FID). Other than being orally bioavailable, the differentiation of PHD inhibitors from recombinant human erythropoietin (rhEPO) has not been demonstrated.

EXPERIMENTAL APPROACH:

JNJ-42905343 was identified and characterized as a novel inhibitor of PHD and its action was compared with rhEPO in healthy rats and in a rat model of inflammation-induced anaemia and FID [peptidoglycan-polysaccharide (PGPS) model].

KEY RESULTS:

Oral administration of JNJ-42905343 to healthy rats increased the gene expression of cytochrome b (DcytB) and divalent metal-ion transporter 1 (DMT1) in the duodenum, and increased plasma EPO. Repeated administration of JNJ-42905343 for 28 days increased blood haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). The serum iron concentration was increased with low doses (0.3 mg·kg(-1) ) but reduced at high doses (6 mg·kg(-1) ). In PGPS-treated rats, administration of JNJ-42905343 for 28 days corrected FID and anaemia, as reflected by increased blood haemoglobin, MCH and MCV. Increased expression of DcytB and DMT1 genes in the duodenum resulting in increased iron availability was defined as the mechanism for these effects. rhEPO did not affect DcytB and DMT1 and was not effective in PGPS-treated rats.

CONCLUSIONS AND IMPLICATIONS:

PHD inhibition has a beneficial effect on iron metabolism in addition to stimulating the release of EPO. Small-molecule inhibitors of PHD such as JNJ-42905343 represent a mechanism distinct from rhEPO to treat anaemia and FID.

• Authors: Terrance D Barrett, Heather L Palomino, Theresa I Brondstetter, Kimon C Kanelakis, Xiaodong Wu, Wen Yan, Katherine P Merton, Freddy Schoetens, Jing Ying Ma, Judy Skaptason, Jingjin Gao, Da-Thao Tran, Hariharan Venkatesan, Mark D Rosen, Nigel P Shankley, Michael H Rabinowitz
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 16 Pg. 4078-88 (Aug 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25988595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The British Pharmacological Society.

Chemical References

• Cation Transport Proteins
• Hemoglobins
• JNJ-42905343
• Peptidoglycan
• Prolyl-Hydroxylase Inhibitors
• Pyrazoles
• Quinazolinones
• solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
• Erythropoietin
• Cytochromes b
• Iron

Topics

• Anemia (blood, drug therapy, genetics, metabolism)
• Animals
• Cation Transport Proteins (genetics)
• Cytochromes b (genetics)
• Duodenum (drug effects, metabolism)
• Erythrocyte Indices (drug effects)
• Erythropoietin (blood, genetics, pharmacology, therapeutic use)
• Female
• Gene Expression (drug effects)
• Hemoglobins (analysis)
• Inflammation (blood, chemically induced, complications, genetics, metabolism)
• Iron (blood)
• Kidney (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Peptidoglycan
• Prolyl-Hydroxylase Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Pyrazoles (pharmacokinetics, pharmacology, therapeutic use)
• Quinazolinones (pharmacokinetics, pharmacology, therapeutic use)
• Rats, Inbred Lew