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T. Miyazawa, E. Kubo, S. Tsuzuki, D.P. Singh, Y. Akagi; Expression of P–glycoprotein/Multidrug Resistance 1 in Lens of Galactose–fed Rats and Its Associationwith Polyol pathway. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1701.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The multidrug resistance P–glycoprotein (Pgp), a plasma membrane located efflux pump, confers multidrug resistance in cells and tumors by virtue of its ability to exclude chemotherapeutic drugs and cytotoxic molecules from cells in an ATP–hydrolysis–dependent fashion. Pgp also appears to modulate the activity of cell swelling activated chrolide channels in many types of cells and tissue including lens. Recently, role of Pgp have been shown in lens volume regulation and initiation of osmotic cataract. Sugar cataract causes osmotic swelling of lens fibers following the accumulation of polyols. Aldose reductase (AR) is a major enzyme that converts glucose to sorbitols in polyol pathway. We hypothesize that Pgp may play a functional role in sugar cataract against osmotic stress by controlling osmo–regulation. In the present study we examined the lenticular expression levels of Pgp in galactose–fed rats, an experimental model for sugar cataract. Methods: Western analysis and quantitative RT–PCR were used to assess Pgp and AR proteins and mRNAs expression levels in galactose–fed rats. AR inhibitor, SNK–860 was used to inhibit sugar cataract in galactose–fed rats. Localization of Pgp was ascertained with immunohistochemistry using anti–Pgp antibodies. Results:: Elevated expression of Pgp mRNA was observed at 4th day in rat lenses after galactose feeding, when mild cortical sugar cataract was observed. However, Pgp mRNA was significantly reduced at 14th day, when severe sugar cataract was appeared. Similarly, expression level of AR protein was increased at 4th day after galactose feeding. However, application of SNK–860, an inhibitor of AR could reverse the changes in Pgp levels in lenses of galactose fed rats confirming the role of AR and involvement of polyol pathway. Conclusions:Pgp expression in rat lens was elevated after galactose–feeding. Our findings suggest that Pgp may be induced by AR over–expression and/or osmotic stress and that play a regulatory role in maintaining osmotic balance in lens fiber.
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