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Smad7 Gene Therapy Ameliorates an Autoimmune Crescentic Glomerulonephritis in Mice

Shuk-Man Ka^*, Xiao-Ru Huang, Hui-Yao Lan, Pei-Yi Tsai, Shun-Min Yang, Hao-Ai Shui and Ann Chen^*

^* Department of Pathology, Tri-Service General Hospital, Graduate Institute of Medical Sciences, and Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China; and Center for Inflammatory Diseases and Molecular Therapies, University of Hong Kong Li Kat Shing Faculty of Medicine, Hong Kong

Address correspondence to: Dr. Ann Chen, Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gung Road, Taipei, Taiwan, ROC. Phone: +886-2-8792-7008; Fax: +886-2-8792-7009; E-mail: doc31717{at}ndmctsgh.edu.tw

Received for publication August 25, 2006. Accepted for publication March 21, 2007.

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF- signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 x DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble–mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-B activation (P < 0.01), thereby inhibiting -smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1 and IL-6), adhesion molecule/chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4⁺ cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673