| First Author | Ka SM | Year | 2012 |
| Journal | Diabetologia | Volume | 55 |
| Issue | 2 | Pages | 509-19 |
| PubMed ID | 22086159 | Mgi Jnum | J:181806 |
| Mgi Id | MGI:5314198 | Doi | 10.1007/s00125-011-2364-5 |
| Citation | Ka SM, et al. (2012) Kidney-targeting Smad7 gene transfer inhibits renal TGF-beta/MAD homologue (SMAD) and nuclear factor kappaB (NF-kappaB) signalling pathways, and improves diabetic nephropathy in mice. Diabetologia 55(2):509-19 |
| abstractText | AIMS/HYPOTHESIS: The TGF-beta/MAD homologue (SMAD) and nuclear factor kappaB (NF-kappaB) 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-kappaB-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-kappaB 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-kappaB signalling pathways. |
