Chronic
hypoxia, a key stimulus for neovascularization, has been implicated in the pathology of proliferative
diabetic retinopathy,
retinopathy of prematurity, and wet
age related macular degeneration. The aim of the present study was to determine the effect of chronic
hypoxia on
drug transporter
mRNA expression and activity in ocular barriers. Sprague-Dawley rats were exposed to hypobaric
hypoxia (PB = 380 mmHg) for 6 weeks, and neonatal calves were maintained under hypobaric
hypoxia (PB = 445 mmHg) for 2 weeks. Age matched controls for rats, and calves were maintained at ambient altitude and normoxia. The effect of
hypoxia on transporter expression was analyzed by qRT-PCR analysis of transporter
mRNA expression in hypoxic and control rat choroid-retina. The effect of
hypoxia on the activity of
PEPT, OCT, ATB(0+), and MCT transporters was evaluated using in vitro transport studies of model transporter substrates across calf cornea and sclera-choroid-RPE (SCRPE). Quantitative gene expression analysis of 84 transporters in rat choroid-retina showed that 29 transporter genes were up regulated or down regulated by ≥1.5-fold in
hypoxia. Nine
ATP binding cassette (ABC) families of efflux transporters including MRP3, MRP4, MRP5, MRP6, MRP7, Abca17,
Abc2, Abc3, and RGD1562128 were up-regulated. For solute carrier family transporters, 11 transporters including SLC10a1, SLC16a3, SLC22a7, SLC22a8, SLC29a1, SLC29a2, SLC2a1, SLC3a2, SLC5a4, SLC7a11, and SLC7a4 were up regulated, while 4 transporters including SLC22a2, SLC22a9, SLC28a1, and SLC7a9 were down-regulated in
hypoxia. Of the three
aquaporin (Aqp)
water channels, Aqp-9 was down-regulated, and Aqp-1 was up-regulated during
hypoxia. Gene expression analysis showed down regulation of OCT-1, OCT-2, and ATB(0+) and up regulation of MCT-3 in hypoxic rat choroid-retina, without any effect on the expression of PEPT-1 and PEPT-2. Functional activity assays of
PEPT, OCT, ATB(0+), and MCT transporters in calf ocular tissues showed that
PEPT, OCT, and ATB(0+) functional activity was down-regulated, whereas MCT functional activity was up-regulated in hypoxic cornea and SCRPE. Gene expression analysis of these transporters in rat tissues was consistent with the functional transport assays except for
PEPT transporters. Chronic
hypoxia results in significant alterations in the
mRNA expression and functional activity of solute transporters in ocular tissues.