Drug Res (Stuttg)
DOI: 10.1055/a-1542-8531
Original Article

Hepcidin inhibition improves iron homeostasis in ferrous sulfate and LPS treatment model in mice

Vishal Patel
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
,
Amit Joharapurkar
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
,
Samadhan Kshirsagar
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
,
Maulik Patel
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
,
Hiren Patel
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
,
Hardikkumar Savsani
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
,
Mukul Jain
1  Zydus Research Centre, Cadila Healthcare Limited, Moraiya, Ahmedabad, India
› Author Affiliations

Abstract

Background Hepcidin, a liver-derived peptide, regulates the absorption, distribution, and circulation of iron in the body. Inflammation or iron overload stimulates hepcidin release, which causes the accumulation of iron in tissues. The inadequate levels of iron in circulation impair erythropoiesis. Inhibition of hepcidin may increase iron in circulation and improve efficient erythropoiesis. Activin-like kinase (ALK) inhibitors decrease hepcidin.

Methods In this work, we have investigated an ALK inhibitor LDN193189 for its efficacy in iron homeostasis. The effect of LDN193189 treatment was assessed in C57BL6/J mice, in which hepcidin was induced by either ferrous sulfate or lipopolysaccharide (LPS) injection.

Results After two hours of treatment, ferrous sulfate increased serum and liver iron, serum hepcidin, and liver hepcidin expression. On the other hand, LPS reduced serum iron in a dose-related manner after six hours of treatment. LDN193189 treatment increased serum iron, decreased spleen and liver iron, decreased serum hepcidin and liver hepcidin expression in ferrous sulfate-treated mice, and increased serum iron in LPS-induced hypoferremia. We observed that ferrous sulfate caused a significantly higher increase in liver iron, serum hepcidin, and liver hepcidin than turpentine oil or LPS in mice. Iron dextran (intraperitoneal or intravenous) increased serum iron, but LDN193189 did not show hyperferremia with iron dextran stimulus.

Conclusion Ferrous sulfate-induced hyperferremia can be a valuable and rapid screening model for assessing the efficacy of hepcidin inhibitors.



Publication History

Received: 05 June 2021

Accepted: 28 June 2021

Publication Date:
26 July 2021 (online)

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