title: The protective role of Smad7 in diabetic kidney disease: mechanism and therapeutic potential.
abstract: OBJECTIVE
  Although Smad3 has been considered as a downstream mediator of transforming growth factor-β (TGF-β) signaling in diabetes complications, the role of Smad7 in diabetes remains largely unclear. The current study tests the hypothesis that Smad7 may play a protective role and has therapeutic potential for diabetic kidney disease.
  
  
  METHODS
  Protective role of Smad7 in diabetic kidney disease was examined in streptozotocin-induced diabetic mice that have Smad7 gene knockout (KO) and in diabetic rats given Smad7 gene transfer using an ultrasound-microbubble-mediated technique.
  
  
  RESULTS
  We found that mice deficient for Smad7 developed more severe diabetic kidney injury than wild-type mice as evidenced by a significant increase in microalbuminuria, renal fibrosis (collagen I, IV, and fibronectin), and renal inflammation (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], monocyte chemoattractant protein-1 [MCP-1], intracellular adhesion molecule-1 [ICAM-1], and macrophages). Further studies revealed that enhanced renal fibrosis and inflammation in Smad7 KO mice with diabetes were associated with increased activation of both TGF-β/Smad2/3 and nuclear factor-κB (NF-κB) signaling pathways. To develop a therapeutic potential for diabetic kidney disease, Smad7 gene was transferred into the kidney in diabetic rats by an ultrasound-microbubble-mediated technique. Although overexpression of renal Smad7 had no effect on levels of blood glucose, it significantly attenuated the development of microalbuminuria, TGF-β/Smad3-mediated renal fibrosis such as collagen I and IV and fibronectin accumulation and NF-κB/p65-driven renal inflammation including IL-1β, TNF-α, MCP-1, and ICAM-1 expression and macrophage infiltration in diabetic rats.
  
  
  CONCLUSIONS
  Smad7 plays a protective role in diabetic renal injury. Overexpression of Smad7 may represent a novel therapy for the diabetic kidney complication.
authors.affiliation: Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hai Yong
authors.initials: HY
authors.lastname: Chen
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Wansheng
authors.initials: W
authors.lastname: Wang
authors.forename: Jin Hua
authors.initials: JH
authors.lastname: Li
authors.forename: Rainer L
authors.initials: RL
authors.lastname: Heuchel
authors.forename: Arthur C K
authors.initials: AC
authors.lastname: Chung
authors.forename: Hui Yao
authors.initials: HY
authors.lastname: Lan
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D051906:Smad7 Protein