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Sci Rep. 2019 Nov 6;9(1):16121. doi: 10.1038/s41598-019-52508-8.

Hif1a and Hif2a can be safely inactivated in cone photoreceptors.

Author information

1
Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, CH-8952, Switzerland. marijana.samardzija@usz.uzh.ch.
2
Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Schlieren, CH-8952, Switzerland.
3
Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, CH-8006, Switzerland.
4
Neuroscience Center Zurich, University of Zurich, Zurich, CH-8006, Switzerland.

Abstract

Impaired tissue oxygenation results in hypoxia and leads to the activation of hypoxia-inducible transcription factors (HIF). A chronic, HIF-triggered molecular response to hypoxia may be an important factor in the etiology of age-related macular degeneration (AMD) and is likely activated before any clinical manifestation of the disease. Thus, HIF1 and HIF2 recently emerged as potential therapeutic targets for AMD. To address and evaluate potential consequences of anti-HIF therapies for retinal physiology and function, we generated mouse lines that have Hif1a, or both Hif1a and Hif2a ablated specifically in cone photoreceptors. The knockdown of Hifs in cones did not cause detectable pathological alterations such as loss of cone photoreceptors, retinal degeneration or abnormalities of the retinal vasculature, had no impact on retinal function and resulted in a similar tolerance to hypoxic exposure. Our data indicate that HIF transcription factors are dispensable for maintaining normal cone function and survival in retinas of adult mice. This study provides the groundwork necessary to establish safety profiles for strategies aiming at antagonizing HIF1A and HIF2A function in cone photoreceptors for the treatment of retinal degenerative diseases that involve a hypoxic component such as AMD.

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