Functional significance of non-erythroid hemoglobin subunits in retinal oxidative stress

The retinal pigment epithelium (RPE) is a critical regulator of retinal homeostasis and a major target of oxidative injury in ischemic retinopathies. Reduced retinal perfusion promotes hypoxia-driven oxidative stress, culminating in pathological neovascularization and vision loss. Although hemoglobin (Hb) is classically restricted to erythrocytes, emerging evidence demonstrates expression of Hb subunits in multiple non-erythroid tissues. Our laboratory has identified robust α-, β-, and γ-globin expression in the RPE, suggesting a previously unrecognized role for non-erythroid Hb in retinal redox regulation. Under physiological conditions, Hb may function as a local oxygen buffer and antioxidant; however, under sustained oxidative stress, oxidized Hb species (metHb, ferrylHb) transition from protective to deleterious, promoting generation of reactive oxygen species and heme-mediated cytotoxicity. To examine the functional relevance of Hb expression in the RPE, we exposed ARPE-19 cells to oxidative stressors including cigarette smoke extract (CSE), sodium iodate (SI), and hypoxic conditions and assessed viability using MTT assays at 24 and 48 hours. All stressors significantly reduced cell viability compared with baseline. To determine how hemoglobin genotype modulates RPE susceptibility to oxidative injury, we utilized Townes mouse models expressing normal hemoglobin (HbAA), sickle cell trait (HbAS), and sickle cell disease hemoglobin (HbSS). Primary RPE cells were isolated from these mice and treated with CSE and SI across a range of doses. Similar to ARPE-19 cells, oxidative stress reduced viability in all genotypes. We then evaluated stress-induced changes in Hb subunit expression in primary RPE from HbAA and HbAS mice following SI exposure. qPCR analysis revealed divergent regulation: α-globin expression increased in AA-RPE but decreased in AS-RPE, while β-globin expression was reduced in both genotypes. These findings suggest that hemoglobin genotype alters globin subunit responses to oxidative stress, potentially modifying RPE redox homeostasis. This work addresses a critical health disparity: individuals of Black or African descent experience worse retinal outcomes in comparison to the general population. Hemoglobin variants such as sickle cell trait, highly prevalent in these populations, may compromise physiologic resilience to chronic oxidative stress, contributing to disproportionate disease burden. By uncovering this link, our findings highlight a previously unrecognized factor in retinal health and lay the groundwork for precision-based strategies to reduce vision loss in high-risk groups. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.