Ocular Roles Of Aquaporins Outside Of The Cornea

Aquaporins and Intraocular Pressure

The ciliary epithelium is a tissue bilayer consisting of pigmented ciliary epithelia (PCE) and non-pigmented ciliary epithelia, whose apical surfaces are juxtaposed, and basolateral surfaces face the ciliary body and aqueous humor, respectively. The principal determinants of intraocular pressure (IOP) are the rates of aqueous fluid production by the ciliary epithelium and aqueous fluid drainage (outflow) in the canal of Schlemm. Aqueous fluid production involves near-isosmolar water secretion across the ciliary epithelium into the posterior aqueous chamber. Aqueous fluid is drained by pressure-driven bulk fluid flow into the canal of Schlemm and across the sclera. Non-pigmented ciliary epithelial cells coexpress AQP1 and AQP4 (30-33), suggesting their involvement in aqueous fluid production. An initial study on human ciliary epithelial cell cultures reported AQP1 protein expression and partial sensitivity of fluid transport to Hg2+ and AQP1 small interfering RNA (siRNA), suggesting AQPl-dependent aqueous inflow (34). Intraocular pressure measurements in mice using a fluid-filled microneedle inserted into the anterior chamber showed a modest reduction in pressure by 2-3 mm Hg in mice lacking AQP1 and/or AQP4 compared to wild-type mice (14). Aquaporin 1 is also expressed in trabecular meshwork endothelium in the canal of Schlemm, where a role in cellular volume regulation has been proposed (35). However, direct measurement of aqueous fluid outflow in mice by a pulsed infusion method showed no effect of AQP1 deletion (14). Together with measurements of aqueous fluid production by a fluorescein iontophoresis-confocal detection method, it was concluded that reduced IOP in AQP-deficient mice was due to reduced aqueous fluid production by the ciliary epithelium. Whether AQP1/AQP4 inhibition will be therapeutically useful in the treatment of glaucoma remains to be determined.

Aquaporin 1 and Cataract Formation

Like the AQP1-expressing corneal endothelium covering the corneal inner surface as discussed further in below, the anterior surface of the lens is covered by an AQP1-

expressing epithelium. Based on immunohistochemical evidence showing AQP1 expression in epithelial cells at the anterior pole of the lens, the involvement of AQP1 in lens epithelial water permeability and cataract formation was tested (36). Osmotic water permeability, measured in calcein-stained epithelial cells in intact lenses from fluorescence changes in response to osmotic gradients, was reduced approximately threefold in lenses from AQP1-null mice. Aquaporin 1 deletion did not alter baseline lens morphology or transparency, though basal water content was significantly increased in AQP1-null mice as measured by gravimetry using kerosene-bromoben-zene gradients and wet/dry weight ratios. Cataract formation was induced in vitro by incubation of lenses in a high-glucose solution. Loss of lens transparency was greatly accelerated in AQP1-null lenses bathed in a 55 mM glucose solution for 18 hours, as measured by optical contrast analysis of transmitted grid images. Cataract formation in vivo was significantly accelerated in a mouse model of acetaminophen toxicity. Aquaporin 1 thus facilitates the maintenance of lens transparency and opposes cataract formation, suggesting the possibility of AQP1 induction to retard cataractogenesis. As mentioned above, an association between AQP0 mutations and cataracts is well established. Recent data suggests AQP0-functioning in lens fiber cells as a pH- and calcium-related water channel (37), though the link between lens fiber water permeability and lens opacification is not known.

Aquaporin 4 and Retinal Signal Transduction and Edema Following Injury

Aquaporin 4 is strongly expressed in Müller cells, especially in perivascular and end-feet processes (facing the retinal capillaries and vitreous body), where it has been proposed to form a multiprotein complex involving the inwardly rectifying K+ channel, Kir4.1 (38, 39). Analogous to its roles in brain astroglial cells and cochlear supportive cells (40), Müller-cell AQP4 has been proposed to maintain extracellular space volume and K+ concentration during bipolar cell excitation. Aquaporin 4-null mice exhibit mildly altered retinal signal transduction as evidenced by reduced electroretinogram (ERG) b-wave amplitude and latency (21), suggesting functional coupling between water and K+ clearance. Aquaporin 4 deletion in Müller cells also provides protection against edema and ganglion cell death following retinal ischemia (17). Aquaporin 4 inhibitors might therefore limit inner retinal pathology following vascular-occlusive and other ischemic diseases causing cytotoxic (cellular) edema.

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