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HIF-1: An Age-Dependent Regulator of Lens Cell Proliferation

¹From the Departments of Ophthalmology and Visual Sciences, ²Surgery, and ⁴Cell Biology and Physiology, Washington University, St. Louis, Missouri; and the ³Division of Biological Sciences, University of California San Diego, La Jolla, California.

PURPOSE. The lens grows throughout life, and lens size is a major risk factor for nuclear and cortical cataracts. A previous study showed that the hypoxic environment around the lens suppressed lens growth in older rats. The present study was conducted to investigate the mechanism responsible for the age-dependent decline in lens cell proliferation.

METHODS. Transgenic mice expressing Cre recombinase in the lens were bred to mice containing floxed Hif1a alleles. Transgenic mice expressing oxygen insensitive forms of HIF-1 in lens epithelial cells were exposed to room air or 60% oxygen. Proliferation was measured by BrdU labeling and cell death by using the TUNEL assay. Morphology was assessed in histologic sections. HIF-1 and p27^KIP1 levels were determined by Western blot. The expression of HIF-regulated genes was assessed on microarrays.

RESULTS. Lenses lacking Hif1a degenerated, precluding study in older animals. Breathing 60% oxygen reduced HIF-1 levels and HIF-1-regulated transcripts in lens epithelial cells from young and older lenses. Overexpression of oxygen-insensitive HIF-1 had no effect on lens size, but suppressed increased proliferation in response to oxygen. Systemic injection of the iron chelator, 1,10-phenanthroline prevented the degradation of HIF-1 and reduced oxygen-induced proliferation. Increasing oxygen decreased levels of p27^KIP1 in the epithelial cells of older mice, which was prevented by expressing oxygen-insensitive forms of HIF-1.

CONCLUSIONS. HIF-1 is present and HIF-1 is transcriptionally active throughout life, but suppresses growth only in older lenses. Maintaining elevated levels of p27^KIP1 in older lenses requires HIF-1. p27^KIP1 and other growth regulators may selectively suppress the proliferation of older lens epithelial cells.