Biology subjects

Mohammad, G.

Publications and source records attributed to Mohammad, G..

3 recordsLinked to original sources

bioRxiv2021

PROTECTIVE ROLE FOR SMOOTH MUSCLE CELL HEPCIDIN IN ABDOMINAL AORTIC ANEURYSM

RationaleHepcidin (HAMP) is a hormone produced primarily in the liver. It controls systemic iron homeostasis by inhibiting the iron exporter ferroportin (FPN) in the gut and spleen, respective sites of iron absorption and recycling. HAMP and FPN are also found ectopically in tissues not involved in systemic iron homeostasis. The physiological functions of ectopic HAMP and FPN are only just beginning to be uncovered. We observed that HAMP expression is markedly increased in smooth muscle cells (SMCs) of abdominal aortic aneurysms (AAA), both in patients and in an experimental mouse model of AAA. ObjectiveTo understand the role of SMC-derived HAMP in the pathophysiology of AAA. Methods and ResultsWe generated mice harbouring an inducible, SMC-specific deletion of the hamp gene. We then applied the experimental model of AAA and simultaneously induced deletion of hamp in SMCs. We found that these mice developed large aneurysms and had greater incidences of rupture and of fatal dissection than mice with intact hamp in SMCs. A similar phenotype was observed in mice harbouring an inducible SMC-specific knock-in of HAMP-resistant FPNC326Y. Additionally, we observed that expression of Lipocalin-2 (LCN2), a protein known to promote AAA, was suppressed in AAA tissue from patients and from mice with intact hamp in SMCs, but not in mice lacking hamp in SMCs. Treatment of these mice with a LCN2-neutralising antibody protected them from the otherwise detrimental effects of loss of hamp in SMCs. ConclusionsThe present study demonstrates that the rise in SMC-derived HAMP within the aneurysm tissue is protective in the setting of AAA, and that such protection involves the cell-autonomous action of HAMP, and suppression of local LCN2. These findings are the first example of a protective role for ectopic HAMP in disease. They expand understanding of the multifaceted functions of HAMP outside the liver.

physiology↗

bioRxiv2020

The renal hepcidin/ferroportin axis controls iron reabsorption and determines renal and hepatic susceptibility to iron overload

The hepcidin/ferroportin axis controls systemic iron homeostasis by regulating iron acquisition from the duodenum and the reticuloendothelial system, respective sites of iron absorption and recycling. Ferroportin is also abundant in the kidney, where it has been implicated in iron reabsorption. However, it remains unknown whether hepcidin regulates ferroportin-mediated iron reabsorption and whether such regulation is important for systemic iron homeostasis. To address these questions, we generated a novel mouse model with an inducible renal-tubule specific knock-in of fpnC326Y, which encodes a hepcidin-resistant FPNC326Y. Under iron-replete conditions, female mice harbouring this allele had lower renal iron content and higher serum and liver iron levels than controls. Under conditions of excess iron availability, male and female mice harbouring this allele had greater liver iron overload, but lower renal iron overload relative to controls. In addition, hemochromatosis mice harbouring a ubiquitous knock-in of fpnC326Y did not develop renal iron overload otherwise seen in the setting of excess iron availability. These findings are the first formal demonstration that hepcidin regulates ferroportin-mediated iron reabsorption. They also show that loss of this regulation contributes to liver iron overload while protecting the kidney in the setting of hemochromatosis. Our findings have important implications. First, they indicate that targeting the hepcidin/ferroportin axis for treating iron overload disorders will inhibit iron reabsorption and increase renal iron content. Second, they suggest that inhibition of iron reabsorption by raised hepcidin in chronic inflammatory conditions contributes to iron deficiency and that parenteral iron supplementation in this setting may cause renal iron overload.

physiology↗

bioRxiv2019

Fetal liver hepcidin supports acquisition of iron stores in utero

In the adult, the liver-derived hormone hepcidin (HAMP) controls systemic iron levels by blocking the iron-exporting protein ferroportin (FPN) in the gut and spleen, the sites of iron absorption and recycling respectively. Impaired HAMP expression or FPN responsiveness to HAMP result in iron overload. HAMP is also expressed in the fetal liver but its role in controlling fetal iron stores is not understood. To address this question in a manner that safeguards against the confounding effects of altered maternal iron homeostasis, we generated fetuses harbouring a paternally-inherited ubiquitous knock-in of the HAMP-resistant fpnC326Y. Additionally, to safeguard against any confounding effects of altered placental iron homeostasis, we generated fetuses with a liver-specific knock-in of fpnC326Y or knockout of the hamp gene. These fetuses had reduced liver iron stores, and markedly increased FPN in the liver, but not in the placenta. Thus, in contrast to the adult, fetal liver HAMP operates cell-autonomously to increase fetal liver iron stores. Our findings also suggest that FPN in the placenta is permissive rather than regulatory of iron transport.

developmental biology↗