Normalization of lens protein kinase Cgamma in galactosemic dogs by a novel aldose reductase inhibitor

• Published in: Veterinary ophthalmology Vol. 7; no. 3; p. 163
• Main Authors: Takemoto, Dolores J, Harris, Richard, Brightman, Al, McGill, John, Hua, Duy, Davidson, Harriet, Fenwick, Brad, Wagner, Lynn M
• Format: Journal Article
• Language: English
• Published: England 01.05.2004
• Subjects: Acetates - administration & dosage; Acetates - therapeutic use; Administration, Oral; Aldehyde Reductase - antagonists & inhibitors; Animals; Benzopyrans - administration & dosage; Benzopyrans - therapeutic use; Blotting, Western - veterinary; DNA Primers; Dog Diseases - drug therapy; Dog Diseases - enzymology; Dog Diseases - pathology; Dogs; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - therapeutic use; Female; Galactosemias - drug therapy; Galactosemias - enzymology; Galactosemias - veterinary; Lens, Crystalline - enzymology; Male; Protein Kinase C - analysis; Protein Kinase C - genetics; Reverse Transcriptase Polymerase Chain Reaction - veterinary; RNA, Messenger - analysis
• ISSN: 1463-5216

The purpose of this study was to determine the effects of a novel aldose reductase inhibitor on lens protein kinase Cgamma (PKCgamma) 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-5alpha,6,8,9-tetrahydro-1-oxopyran[4,3-beta](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. PKCgamma 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. PKCgamma protein levels were reduced in the galactosemic dog lenses, but synthesis of PKCgamma was not affected, as measured by RT-PCR. The PKCgamma 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 PKCgamma mRNA but not in total PKCgamma protein levels. This study demonstrates the use of a novel aldose reductase inhibitor to control changes in PKCgamma in dog lens, a PKC that is known to control gap junction activity.