Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA.
To investigate the role of human aldose reductase (hAR) in the pathogenesis of diabetic complications, we generated transgenic mice carrying hAR cDNA driven by the murine MHC class I molecule promoter (hAR-Tg). Northern and Western blot analyses and immunoassay of hAR revealed that both hAR mRNA and the protein were expressed in all tissues tested. Thrombosis in renal vessels and fibrinous deposits in Bowman's capsule were observed in 6-week-old hAR-Tg mice fed a normal diet. Ingestion of a 30% glucose diet for 5 days caused sorbitol concentrations in the liver, kidney, and muscle of hAR-Tg mice to be elevated significantly. Seven-week-old hAR-Tg mice fed a 20% galactose diet for 7 days developed cataracts and occlusion of the retinochoroidal vessels, in addition to pathological changes in the kidney. Despite an elevated aldose reductase level in hAR-Tg mice and their intake of an aldose diet, no histopathological changes were found in other tissues, including the brain, lungs, heart, thymus, spleen, intestine, liver, muscle, spinal cord, or sciatic nerve. Results suggest that target organs of diabetic complications, such as the kidney, lens, and retina are sensitive to damage associated with a high level of AR expression, but other organs are not; the susceptibility of each organ to diabetic complications is determined by not only hAR but also other factors.
Yamaoka
T
T
Division of Endocrinology and Metabolism, University of Tsukuba, Japan.
Nishimura
C
C
Yamashita
K
K
Itakura
M
M
Yamada
T
T
Fujimoto
J
J
Kokai
Y
Y
D000449:Aldehyde Reductase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D015139:Blotting, Southern; D015153:Blotting, Western; D017931:DNA Primers; D018076:DNA, Complementary; D003925:Diabetic Angiopathies / Q000139:chemically induced / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000473:pathology*; D004040:Dietary Carbohydrates / Q000494:pharmacology; D005260:Female; D005805:Genes, MHC Class I; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D013012:Sorbitol / Q000378:metabolism*
D017931:DNA Primers; D018076:DNA, Complementary; D004040:Dietary Carbohydrates; D012333:RNA, Messenger; D013012:Sorbitol; D000449:Aldehyde Reductase; D005947:Glucose