Latent TGF-beta1 protects against crescentic glomerulonephritis.

Abstract

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.

• Authors: Xiao R Huang, Arthur C K Chung, Li Zhou, Xiao J Wang, Hui Y Lan
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 19 Issue 2 Pg. 233-42 (Feb 2008) ISSN: 1533-3450 [Electronic] United States
• PMID: 18216320 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Smad7 Protein
• Smad7 protein, mouse
• Transcription Factor RelA
• Transforming Growth Factor beta1
• Tumor Necrosis Factor-alpha
• Complement System Proteins

Topics

• Animals
• Chemokine CCL2 (metabolism)
• Complement System Proteins (metabolism)
• Disease Models, Animal
• Fibrosis
• Glomerular Basement Membrane (immunology, metabolism, pathology)
• Glomerulonephritis (immunology, pathology, physiopathology)
• Humans
• Keratinocytes (physiology)
• Macrophages (pathology)
• Mice
• Mice, Inbred ICR
• Mice, Transgenic
• Proteinuria (immunology, pathology, physiopathology)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Smad7 Protein (metabolism)
• T-Lymphocytes (pathology)
• Transcription Factor RelA (metabolism)
• Transforming Growth Factor beta1 (genetics, immunology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)