title: 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.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Graduate Institute of Aerospace and Undersea Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.
authors.forename: S M
authors.initials: SM
authors.lastname: Ka
authors.forename: Y C
authors.initials: YC
authors.lastname: Yeh
authors.forename: X R
authors.initials: XR
authors.lastname: Huang
authors.forename: T K
authors.initials: TK
authors.lastname: Chao
authors.forename: Y J
authors.initials: YJ
authors.lastname: Hung
authors.forename: C P
authors.initials: CP
authors.lastname: Yu
authors.forename: T J
authors.initials: TJ
authors.lastname: Lin
authors.forename: C C
authors.initials: CC
authors.lastname: Wu
authors.forename: H Y
authors.initials: HY
authors.lastname: Lan
authors.forename: A
authors.initials: A
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D048909:Diabetes Complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D003928:Diabetic Nephropathies / Q000378:metabolism*; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D016328:NF-kappa B / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014465:Ultrasonics
chemical_list: D016328:NF-kappa B; D051785:Smad Proteins; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta
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