Kidney-targeting Smad7 gene transfer inhibits renal TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways, and improves diabetic nephropathy in mice
Aims/hypothesis The TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) 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 g...
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Veröffentlicht in: | Diabetologia 2012-02, Vol.55 (2), p.509-519 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | Aims/hypothesis
The TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) 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-β/SMAD2/3-mediated fibrosis and NF-κB-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-β/SMAD and NF-κB 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-β/SMAD and NF-κB signalling pathways. |
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ISSN: | 0012-186X 1432-0428 |
DOI: | 10.1007/s00125-011-2364-5 |