Latent TGF-beta1 protects against crescentic glomerulonephritis.
Despite the critical role that TGF-beta plays in renal fibrosis, transgenic mice that overexpress human latent TGF-beta1 in the skin exhibit normal renal histology and function even though circulating levels of latent TGF-beta1 are an order of magnitude higher than wild-type animals. In fact, latent TGF-beta1 seems to protect against renal inflammation in a model of ureteral obstruction. It is unknown, however, whether latent TGF-beta1 also has this effect in immunologically mediated forms of renal disease such as anti-GBM crescentic glomerulonephritis. We induced anti-GBM disease in wild-type and transgenic mice overexpressing latent TGF-beta1 in keratinocytes. After 14 days, wild-type mice developed progressive crescentic glomerulonephritis with severe renal inflammation and fibrosis. In transgenic mice, proteinuria was reduced by 50%, renal function was preserved, and the formation of glomerular crescents was suppressed by 70%. In addition, transgenic animals had reduced renal inflammation, evidenced by a 70% decrease in the accumulation of T cells and macrophages, and reduced expression of renal IL-1beta, TNFalpha, and MCP-1 by 70 to 80%. Progressive renal fibrosis was also prevented in the transgenic mice, and these protective effects were associated with elevated levels of latent, but not active, TGF-beta1 in plasma and renal tissue. Renal Smad7 was up-regulated and both NF-kappaB and TGF-beta/Smad2/3 activation were suppressed. In conclusion, mice overexpressing latent TGF-beta1 in the skin were protected against anti-GBM crescentic glomerulonephritis, possibly via Smad 7-mediated inhibition of NF-kappaB-dependent renal inflammation and TGF-beta/Smad2/3-dependent fibrosis.
Huang
Xiao R
XR
Department of Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.
Chung
Arthur C K
AC
Zhou
Li
L
Wang
Xiao J
XJ
Lan
Hui Y
HY
D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D050533:Glomerular Basement Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D011507:Proteinuria / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins