Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice.
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-beta/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-beta 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-kappaB activation (P < 0.01), thereby inhibiting alpha-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1beta 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.
Ka
Shuk-Man
SM
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325 Sec. 2 Cheng-Gung Road, Taipei, Taiwan, ROC.
Huang
Xiao-Ru
XR
Lan
Hui-Yao
HY
Tsai
Pei-Yi
PY
Yang
Shun-Min
SM
Shui
Hao-Ai
HA
Chen
Ann
A
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005921:Glomerulonephritis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D045423:Microbubbles; D016328:NF-kappa B / Q000378:metabolism; D011507:Proteinuria / Q000235:genetics / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014465:Ultrasonics
D016328:NF-kappa B; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta