Galactosemic neuropathy in transgenic mice for human aldose reductase.
We studied the functional consequences of an enhanced polyol pathway activity, elicited with galactose feeding, on the peripheral nerve of transgenic mice expressing human aldose reductase. Nontransgenic littermate mice were used as controls. With a quantitative immunoassay, the expression level of human aldose reductase in the sciatic nerve was 791 +/- 44 ng/mg protein (mean +/- SE), about 25% of that in human sural nerve. When the transgenic mice were fed food containing 30% galactose, significant levels of galactitol accumulated in the sciatic nerve. Galactose feeding of nontransgenic littermate mice led to a 10-fold lower accumulation of galactitol. Galactose feeding for 16 weeks caused a significant and progressive decrease in motor nerve conduction velocity in transgenic mice to 80% of the level of galactose-fed littermate mice, which was not significantly different from that of galactose-free littermate mice. A morphometric analysis of sciatic nerve detected > 10% reduction of mean myelinated fiber size but no alterations of myelinated fiber density in galactose-fed transgenic mice compared with other groups. The functional and structural changes that develop in galactose-fed transgenic mice are similar to those previously reported in diabetic animals. The results of these studies suggest that transgenic mice expressing human aldose reductase may be a useful model not only for defining the role of the polyol pathway in diabetic neuropathy but also for identifying and characterizing effective inhibitors specific for human aldose reductase.
Yagihashi
S
S
Department of Pathology, Hirosaki University School of Medicine, Japan.
Yamagishi
S
S
Wada
R
R
Sugimoto
K
K
Baba
M
M
Wong
H G
HG
Fujimoto
J
J
Nishimura
C
C
Kokai
Y
Y
D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D004376:Galactitol / Q000096:biosynthesis; D005690:Galactose / Q000008:administration & dosage; D005693:Galactosemias / Q000201:enzymology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009431:Neural Conduction; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D012584:Sciatic Nerve / Q000201:enzymology / Q000378:metabolism
D017931:DNA Primers; D004376:Galactitol; D000449:Aldehyde Reductase; D005690:Galactose