The Protective Role of Smad7 in Diabetic Kidney Disease: Mechanism and Therapeutic Potential

OBJECTIVE-Although Smad3 has been considered as a downstream mediator of transforming growth factor-beta (TGF-beta) 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. RESEARCH DESIGN AND 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-1 beta [IL-1 beta], tumor necrosis factor-alpha [TNF-alpha], 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-beta/Smad2/3 and nuclear factor-kappa B (NF-kappa B) 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-beta/Smad3-mediated renal fibrosis such as collagen I and IV and fibronectin accumulation and NF-kappa B/p65-driven renal inflammation including IL-1 beta, TNF-alpha, 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. Diabetes 60:590-601, 2011