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1 oligodeoxynucleotides reduces
kidney weight and matrix mRNAs in diabetic mice
Renal-Electrolyte and Hypertension Division and Penn Center for Molecular Studies of Kidney Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6144
Inhibition of
gene expression by antisense oligodeoxynucleotides (ODNs) relies on
their ability to bind complementary mRNA sequences and prevent
translation. The proximal tubule is a suitable target for ODN therapy
in vivo because circulating ODNs accumulate in the proximal tubule in
high concentrations. Because increased proximal tubular transforming
growth factor- 
1 (TGF-1) expression may mediate diabetic renal
hypertrophy, we investigated the effects of antisense TGF-1 ODN on
the high-glucose-induced proximal tubular epithelial cell hypertrophy
in tissue culture and on diabetic renal hypertrophy in vivo. Mouse
proximal tubular cells grown in 25 mM D-glucose and exposed
to sense ODN as control (1 µM) exhibited increased
3[H]leucine incorporation by 120% and total
TGF-1 protein by 50% vs. culture in 5.5 mM D-glucose.
Antisense ODN significantly decreased the high-glucose-stimulated
TGF-1 secretion and leucine incorporation. Continuous infusion for
10 days of ODN (100 µg/day) was achieved via osmotic minipumps in
diabetic and nondiabetic mice. Sense ODN-treated
streptozotocin-diabetic mice had 15.3% increase in kidney weight, 70%
increase in 
1(IV) collagen and 46% increase in fibronectin mRNA
levels compared with nondiabetic mice. Treatment of diabetic mice with
antisense ODN partially but significantly decreased kidney TGF-1
protein levels and attenuated the increase in kidney weight and the
1(IV) collagen and fibronectin mRNAs. In conclusion, therapy with
antisense TGF-1 ODN decreases TGF-1 production and attenuates
high-glucose-induced proximal tubular cell hypertrophy in vitro and
partially prevents the increase in kidney weight and extracellular
matrix expression in diabetic mice.
transforming growth factor-1; nephropathy; proximal tubule; glucose; collagen type IV; fibronectin; osmotic mini-pumps
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