Activation of the Smad pathway in glomeruli from a spontaneously diabetic rat model, OLETF rats.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) mediates the excess accumulation of extracellular matrix in the diabetic kidney. Smad family proteins have been identified as signal transducers for the TGF-beta superfamily. We sought to characterize the role of Smad proteins in mediating TGF-beta responses in the development of diabetic nephropathy.


METHODS
We evaluated the time course of TGF-beta1 fibronectin, Smad2 and Smad3 protein expression and Smad3 activation in glomeruli from spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using immunohistochemistry and Western blot analysis.


RESULTS
The glomeruli of diabetic OLETF rats showed not only accelerated activation of Smad3, but also enhanced protein expression of Smad2 and Smad3, which occurred in parallel to the increased expression of TGF-beta and fibronectin compared with glomeruli of control, Long-Evans Tokushima Otsuka (LETO) rats at 30 weeks of age. No differences were found in TGF-beta1 fibronectin, Smad2 and Smad3 protein expression and Smad3 activation in glomeruli between the two strains at 12 weeks of age when OLETF rats were not diabetic.


CONCLUSIONS
The enhancement of Smad protein expression and activation may be involved in the TGF-beta signaling cascade that plays an important role in the development of diabetic nephropathy through progressive expansion of the mesangial matrix.
Furuse
Yoko
Y
Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Hashimoto
Naotake
N
Maekawa
Mamiko
M
Toyama
Yoshiro
Y
Nakao
Atsuhito
A
Iwamoto
Itsuo
I
Sakurai
Kenichi
K
Suzuki
Yoshifumi
Y
Yagui
Kazuo
K
Yuasa
Shigeki
S
Toshimori
Kiyotaka
K
Saito
Yasushi
Y
D000818:Animals; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007678:Kidney Glomerulus; D008297:Male; D051381:Rats; D020334:Rats, Inbred OLETF; D015398:Signal Transduction; D051899:Smad2 Protein / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D051900:Smad3 Protein / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D005353:Fibronectins; D051899:Smad2 Protein; D051900:Smad3 Protein; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1