期刊
DIABETOLOGIA
卷 55, 期 2, 页码 509-519出版社
SPRINGER
DOI: 10.1007/s00125-011-2364-5
关键词
db/db mice; Diabetic nephropathy; Endothelial cell; Podocyte; SMAD7; Type 2 diabetes; Ultrasound-mediated microbubble-inducible gene transfer
资金
- Tri-Service General Hospital [TSGH-C98-53]
- Department of Health, Executive Yuan [DOH97-TD-I-11-TM006]
- Ministry of Economic Affairs, Taiwan, Republic of China [99-EC-17-A-19-S1-161]
Aims/hypothesis The TGF-beta/MAD homologue (SMAD) and nuclear factor kappa B (NF-kappa B) signalling pathways have been shown to play a critical role in the development of renal fibrosis and inflammation in diabetic nephropathy. We therefore examined whether targeting these pathways by a kidney-targeting Smad7 gene transfer has therapeutic effects on renal lesions in the db/db mouse model of type 2 diabetes. Methods We delivered Smad7 plasmids into the kidney of db/db mice using kidney-targeting, ultrasound-mediated, microbubble-inducible gene transfer. The histopathology, ultrastructural pathology and pathways of TGF-beta/SMAD2/3-mediated fibrosis and NF-kappa B-dependent inflammation were evaluated. Results In this mouse model of type 2 diabetes, Smad7 gene therapy significantly inhibited diabetic kidney injury, compared with mice treated with empty vectors. Symptoms inhibited included: (1) proteinuria and renal function impairment; (2) renal fibrosis such as glomerular sclerosis, tubulo-interstitial collagen matrix abundance and renal inflammation, including Inos (also known as Nos2), Il1b and Mcp1 (also known as Ccl2) upregulation, as well as macrophage infiltration; and (3) podocyte and endothelial cell injury as demonstrated by immunohistochemistry and/or electron microscopy. Further study demonstrated that the improvement of type 2 diabetic kidney injury by overexpression of Smad7 was associated with significantly inhibited local activation of the TGF-beta/SMAD and NF-kappa B signalling pathways in the kidney. Conclusions/interpretation Our results clearly demonstrate that kidney-targeting Smad7 gene transfer may be an effective therapy for type 2 diabetic nephropathy, acting via simultaneous modulation of the TGF-beta/SMAD and NF-kappa B signalling pathways.
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