Roles of Hypoxia Response in Retinal Development and Pathophysiology

Abstract

The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia-inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-typespecific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified.

Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model

“…A study reported that fenofibrate prevents pathological neovascularization in the rat OIR model by suppressing HIF and VEGF [26]. HIF plays an important role in maintaining tissue homeostasis after exposure to hypoxic conditions and other stress stimuli [27,28]. Thus, we also focused on the HIF/VEGF system as a potential pathway activated by pemafibrate.…”

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

“…Among the oxygen sensing transcription factors hypoxia-inducible factor 1 (HIF-1) is a heterodimer composed of two subunits: a labile HIF-1α subunit and a stable HIF-1β subunit. Under normoxia, HIF-1α is continuously degraded by proteasome, but when oxygen becomes limiting, HIF-1α escapes degradation, accumulates in the cell, is imported into the nucleus, dimerizes with HIF-1β and activates dozen of genes encoding for a multitude of pro-angiogenic and inflammatory factors that are involved in both excessive vasopermeability and neovessel growth [84]. HIF-1 also activates the expression of genes related to ECM degradation (for Ref., see [85]) and modulates the expression of genes involved in autophagy, apoptosis, redox homeostasis and immunity [86], thus suggesting a role as a multiplicative factor in mediating an abundance of pathological responses to an ischemic insult.…”

Inhibition of the HIF‐1α/BNIP3 pathway has a retinal neuroprotective effect

“…3 Under ocular ischemia or other cellular stress conditions in the retina, retinal HIF can be stabilized, and it induces a pivotal shift in hypoxic retinal cells to undergo neovascularization and/or pathological anaerobic metabolic processes. 5,6 It was reported that focal HIF-1α expression increased with acute retinal ischemia in humans, 7 and an increase in HIF-1α protein expression was also observed in the chronically progressed glaucomatous retina and the optic nerve head. 8 Moreover, HIF inhibition has been suggested to be therapeutic in various experimental ocular diseases including age-related macular degeneration, retinopathy of prematurity, diabetic retinopathy, glaucoma and corneal injuries.…”