TGFβ2-Hepcidin Feed-Forward Loop in the Trabecular Meshwork Implicates Iron in Glaucomatous Pathology

Area of Science:

• Ocular biology
• Glaucoma pathogenesis
• Iron homeostasis

Background:

• Elevated transforming-growth-factor-beta-2 (TGF-β2) in the trabecular meshwork (TM) and aqueous humor is linked to primary open-angle glaucoma (POAG).
• TGF-β2 signaling alters extracellular matrix homeostasis, potentially involving iron metabolism.

Purpose of the Study:

• To investigate whether TGF-β2 upregulates hepcidin, a key regulator of iron homeostasis.
• To explore the role of iron and reactive oxygen species (ROS) in TGF-β2-mediated POAG pathogenesis.

Main Methods:

• Primary human TM cells and ex vivo anterior segment organ cultures were treated with TGF-β2, hepcidin, heparin, or N-acetyl carnosine.
• Gene and protein expression of hepcidin, ferroportin, and ferritin were analyzed using RT-PCR, Western blotting, and immunohistochemistry.
• Reactive oxygen species (ROS) levels were quantified using dihydroethidium.

Main Results:

• TGF-β2 upregulated local hepcidin synthesis in TM cells and tissues.
• Hepcidin downregulated ferroportin, increased ferritin, and elevated iron-catalyzed ROS.
• TGF-β2, hepcidin, and ROS formed a self-sustaining feed-forward loop, which was partially disrupted by heparin and N-acetyl carnosine.

Conclusions:

• A feed-forward loop involving TGF-β2, hepcidin, iron, and ROS contributes to POAG pathogenesis.
• Hepcidin antagonists and antioxidants can disrupt this loop, suggesting potential therapeutic applications.
• Targeting hepcidin may offer a novel therapeutic strategy for TGF-β2-associated POAG.