H₂O₂ induces oxidative stress damage through the BMP‐6/SMAD/hepcidin axis

Abstract

Age-related macular degeneration (AMD) is one of the leading causes of blindness in elderly individuals worldwide. Oxidative stress injury to retinal pigment epithelial (RPE) cells plays a major role in the pathogenesis of AMD. The purpose of this study was to observe the correlation between Hepcidin and neovascular age-related macular degeneration (nAMD) and to further observe whether oxidative stress can inhibit Hepcidin expression through relevant signaling pathways to produce oxidative damage. We compared the concentrations of Hepcidin in the aqueous humor of nAMD patients and a control group and found that the concentration of Hepcidin was lower in nAMD patients. Through PCR and western blotting, we observed that H 2 O 2 can significantly inhibit the expression of Bone morphogenetic protein-6 (BMP-6) andHepcidin and increase the intracellular iron concentration in RPE cells, while BMP-6 can reverse the inhibition of Hepcidin and the increase in iron concentration caused by H 2 O 2 . In addition, alterations in smad1 and smad5 expression were examined, and pretreatment with BMP-6 was demonstrated to reduce H 2 O 2 -induced activation of smad1 and smad5. The effects of BMP-6 were attenuated by smad1 and smad5 siRNA, further verifying that oxidative stress inhibits the expression of Hepcidin by inhibiting activation of the BMP/SMAD signaling pathway. To some extent, this study verified that oxidative stress injury plays a role in nAMD by affecting the level of hepcidin, which lays a foundation for exploring new methods to treat nAMD. K E Y W O R D Sbone morphogenetic protein-6, H 2 O 2 , Hepcidin, neovascular age-related macular degeneration

Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes

“…Experimental support is provided by the induction of GCLC and HMOX1 mRNAs, markers of oxidative stress [32][33][34], in cells exposed to FAC (Figs 1 and 2). Our findings are consistent with the known sensitivity of both BMP/SMAD and JAK/STAT signaling pathways to oxidants [41,42], and the previously described suppression of hepcidin in iron-loaded [14,18,19] and ironloaded/IL-6-treated [43] cultured hepatic cells. Moreover, they provide evidence that the ironmediated suppression of hepcidin in cultured cells is caused by inhibition of basal SMAD signaling.…”

Long-Chain Polyunsaturated Fatty Acids and Their Metabolites Regulate Inflammation in Age-Related Macular Degeneration

“…6 Dry AMD, also named non-neovascular, non-exudative or atrophic AMD, is characterized by the development of drusen, 7 while wet AMD, also known as neovascular or exudative AMD, is characterized by CNV. 8 It is well recognized that AMD is a multifactorial disease, 9,10 including genetic predisposition, 11 oxidative stress, 12,13 neovascularization, 14,15 inflammatory responses 16 and remodeling processes of the retinal extracellular matrix. 17 Rozing et al proposed that the essence of AMD was a series of damages involved in aging and the consequently activated host immune responses to damages.…”

Iron Replacement and Redox Balance in Non-Anemic and Mildly Anemic Iron Deficiency COPD Patients: Insights from a Clinical Trial

“…Moreover, alterations in iron metabolism also take place in other conditions during acute and chronic phases, particularly in hyperinflammatory states [ 11 , 12 ]. Hepcidin, a hormone involved in the regulation of iron flow between plasma and reservoirs and from the gastrointestinal tract, is also a marker of inflammation as an acute phase reactant [ 13 , 14 , 15 ] and can be regulated by many other factors [ 16 , 17 , 18 , 19 ].…”