Acidic milieu augments the expression of hepcidin, the central regulator of iron homeostasis

• Published in: International journal of hematology Vol. 96; no. 6; pp. 701 - 709
• Main Authors: Mizumoto, Chisaki, Kawabata, Hiroshi, Uchiyama, Tatsuki, Sakamoto, Soichiro, Kanda, Junya, Tomosugi, Naohisa, Takaori-Kondo, Akifumi
• Format: Journal Article
• Language: English
• Published: Japan Springer Japan 01.12.2012; Springer; Springer Nature B.V
• Subjects: Acidosis; Acids - pharmacology; Anemia; Anemias. Hemoglobinopathies; Antimicrobial Cationic Peptides - biosynthesis; Antimicrobial Cationic Peptides - genetics; Biological and medical sciences; Carbon Dioxide - pharmacology; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Cellular Microenvironment; Chronic kidney disease; Diseases of red blood cells; Gene Expression Regulation, Leukemic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Hematologic and hematopoietic diseases; Hematology; Hepcidin; Hepcidins; Homeostasis - drug effects; Humans; Hydrochloric Acid - pharmacology; Hydrogen-Ion Concentration; Iron - metabolism; Iron-Regulatory Proteins - biosynthesis; Iron-Regulatory Proteins - genetics; K562 Cells - drug effects; K562 Cells - metabolism; Kidneys; Lactic Acid - pharmacology; Liver Neoplasms - pathology; Medical sciences; Medicine; Medicine & Public Health; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oncology; Original Article; Promoter Regions, Genetic; Renal failure; RNA, Messenger - biosynthesis; RNA, Neoplasm - biosynthesis; Up-Regulation - drug effects; Urinary system involvement in other diseases. Miscellaneous; Chronic kidney disease; Acidosis; Anemia; Hepcidin; Kidney disease; Urinary system disease; Hematology; Homeostasis; Hemopathy; Iron; Acid base balance disorder; Regulator; Metabolic disorder; Renal failure
• ISSN: 0925-5710; 1865-3774; 1865-3774
• DOI: 10.1007/s12185-012-1223-6

Hepcidin is the central regulator of body iron homeostasis, and dysregulation of hepcidin expression causes various clinical disorders, such as anemia and hemochromatosis. Various stimuli, including iron load and interleukin-6, are involved in the regulation of hepcidin expression. We previously reported that serum hepcidin levels were high in patients with end-stage renal disease, compared with healthy subjects. Since metabolic acidosis is commonly observed in these patients, we hypothesized that acidic milieu might augment hepcidin expression. In this study, we investigated the effect of changes in the pH of the microenvironment on hepcidin expression in human hepatoma and leukemia cell lines. We found that hepcidin expression in these cells was augmented by the acidic milieu created with lactic acid, hydrochloric acid and excess carbon dioxide. Acidic milieu did not clearly enhance hepcidin promoter activity, but rather stabilized hepcidin transcript in the hepatoma cells. We speculate that metabolic acidosis may contribute in part to the elevation of serum hepcidin levels in patients with end-stage chronic kidney disease. Further studies are needed to elucidate the association between acidosis and hepcidin expression in various clinical settings.