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Normalization of lens protein kinase Cγ in galactosemic dogs by a novel aldose reductase inhibitor
Author(s) -
Takemoto Dolores J.,
Harris Richard,
Brightman Al,
McGill John,
Hua Duy,
Davidson Harriet,
Fenwick Brad,
Wagner Lynn M.
Publication year - 2004
Publication title -
veterinary ophthalmology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.594
H-Index - 50
eISSN - 1463-5224
pISSN - 1463-5216
DOI - 10.1111/j.1463-5224.2004.04016.x
Subject(s) - aldose reductase inhibitor , galactosemia , aldose reductase , endocrinology , medicine , protein kinase c , aldehyde reductase , enzyme inhibitor , biology , galactose , toxicity , biochemistry , enzyme , diabetes mellitus
The purpose of this study was to determine the effects of a novel aldose reductase inhibitor on lens protein kinase Cγ (PKCγ) levels in galactosemic dogs. Six‐month old Beagles (12 total; 6 male and 6 female) were made galactosemic by feeding a diet of 40% galactose for 6 weeks. Three dogs per group were fed either control, normal diet, 40% galactose diet, 40% galactose diet with aldose reductase inhibitor at 100 mg/kg body weight per day given orally, or a control diet with aldose reductase inhibitor alone (1‐H,7‐H‐5α,6,8,9‐tetrahydro‐1‐oxopyran[4,3‐β] 1 benzopyran, referred to herein as HAR‐1). Lenses were removed and analyzed for toxicity by pathological examination. Lens polyol concentrations were determined by GC/MS. PKCγ levels were determined by Western blot and by reverse transcriptase‐polymerase chain reaction (RT‐PCR). No toxicity was observed from the aldose reductase inhibitor when given at 100 mg/kg body weight per day for 6 weeks. Galactosemic dogs showed deterioration of lens cells. Deterioration included vacuole formation in the lens, cell lysis, and loss of cell nuclei. Galactosemic dogs given the HAR‐1 appeared identical to control dogs. Polyol concentrations in the lenses were reduced by 50% in dogs fed the 40% galactose diet with the aldose reductase inhibitor, HAR‐1. PKCγ protein levels were reduced in the galactosemic dog lenses, but synthesis of PKCγ was not affected, as measured by RT‐PCR. The PKCγ protein levels were similar to controls in dogs given the aldose reductase inhibitor, HAR‐1, even when polyol concentrations remained 50% elevated above control levels. HAR‐1, when given to control dogs, caused a reduction in the synthesis of PKCγ mRNA but not in total PKCγ protein levels. This study demonstrates the use of a novel aldose reductase inhibitor to control changes in PKCγ in dog lens, a PKC that is known to control gap junction activity.