Transforming growth factor-beta1 and Smad4 signaling pathway down-regulates renal extracellular matrix degradation in diabetic rats.
OBJECTIVE
To investigate the role of transforming growth factor-beta1 (TGF-beta1)/Smad4 pathway in development of renal fibrosis in streptozotocin (STZ)-induced diabetic nephropathy (DN) rats and explore its possible mechanism.


METHODS
Male Wistar rats weighing 180-220 g were divided into 5 groups: group A (normal control), group B [diabetes mellitus (DM) 2 weeks], group C (DM 4 weeks), group D (DM 8 weeks), and group E (DM 16 weeks). Except for the normal control group, other groups were induced DM by single injection of STZ (55 mg/kg) respectively. Blood glucose level, serum creatinine, and 24-hour urine protein were examined. Expressions of TGF-beta1 and Smad4 protein and mRNA in kidney were detected using immunohistochemical technique, Western blot, and real-time PCR. mRNA expressions of stromelysin-1 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen In in kidney were also detected by real-time PCR.


RESULTS
The levels of blood glucose, serum creatinine, and 24-hour urine protein in rats of group B, C, D, and E were higher than those of the control group. With the progression of renal fibrosis, the expressions of TGF-beta1 and Smad4 protein and mRNA in kidney of diabetic rats elevated. In addition, the renal MMP-3 mRNA expression diminished in diabetic rats, while TIMP-1 and collagen III mRNA increased.


CONCLUSIONS
In STZ-induced diabetic rats, the TGF-beta1/Smad4 appears to play an important role in renal fibrosis of DN. The increased expression of TGF-beta1 and Smad4 might result in the transcriptional regulation of downstream target genes of TGF-beta1/Smad4 pathway, which contributes to the progression of renal fibrosis in diabetic rats.
Yang
Qin
Q
Department of Pathophysiology, Guiyang Medical College, Guiyang. qinyang@gmc.edu.cn
Xie
Ru-jia
RJ
Yang
Ting
T
Fang
Li
L
Han
Bing
B
Zhang
Guo-zhong
GZ
Cheng
Ming-liang
ML
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015536:Down-Regulation; D005109:Extracellular Matrix / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D051901:Smad4 Protein; D053773:Transforming Growth Factor beta1