Study to establish the role of JAK2 and SMAD1/5/8 pathways in the inhibition of hepcidin by polysaccharides from Angelica sinensis.

Angelica sinensis polysaccharide (ASP) is one of the major active ingredients in Angelica sinensis (Oliv.) Diels. This traditional Chinese medicine has been used for thousands of years for treating gynecological diseases.Previous studies have suggested that ASP from the roots of Angelica sinensis (Oliv.) Diels suppresses hepcidin expression, but the underlying molecular mechanisms are not known. The present study was designed to establish the role of the janus-kinases 2 (JAK2) and son of mothers against decapentaplegic 1/5/8 (SMAD1/5/8) pathways in the inhibition of hepcidin by polysaccharides from Angelica sinensis in normal rats.ASP was administered orally (0.3, 0.6 and 1.2g/kg body weight) to male Sprague-Dawley rats every day for 20 days. Intraperitoneal injections of recombinant human erythropoietin (rhEPO; 800 and 2000U/kg body weight) were given to the positive control group every day for 3 days. After administration, hepcidin levels, blood parameters, serum iron status and non-heme iron concentrations in the liver were examined. Western blot analyses were used to investigate the expression of five relevant signaling proteins in the liver.RhEPO injection significantly stimulated erythropoiesis and expression of the serum transferrin receptor (sTfR), and decreased serum iron status and non-heme iron concentrations in the liver. However, blood parameters barely changed in the ASP groups. sTfR, serum iron, and liver iron levels altered only in the ASP high-dose group (1.2g/kg body weight). rhEPO and ASP significantly reduced hepcidin expression by inhibiting the expression of phospho-SMAD1/5/8 and JAK2 in the liver, but not through transmembrane protease serine 6 (TMPRSS6) and extracellular signal-regulated kinase 1/2 (ERK1/2).These data suggested that ASP can interrupt the JAK2 and SMAD1/5/8 pathways, which eventually results in lower expression of hepcidin.