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Latent TGF-β1 Protects Against Crescentic Glomerulonephritis

Xiao R. Huang^*, Arthur C.K. Chung^*, Li Zhou^*, Xiao J. Wang and Hui Y. Lan^*

^* Department of Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China and Department of Otolaryngology, Oregon Health and Science University, Portland, Oregon

Correspondence: Dr. Hui Y. Lan, Department of Medicine, The University of Hong Kong, L8-39, Laboratory Block, 21 Sassoon Road, Hong Kong. Phone: 852-28199745; Fax: 852-28162095; E-mail: hylan{at}hku.hk

Received for publication April 20, 2007. Accepted for publication August 9, 2007.

Despite the critical role that TGF-β plays in renal fibrosis, transgenic mice that overexpress human latent TGF-β1 in the skin exhibit normal renal histology and function even though circulating levels of latent TGF-β1 are an order of magnitude higher than wild-type animals. In fact, latent TGF-β1 seems to protect against renal inflammation in a model of ureteral obstruction. It is unknown, however, whether latent TGF-β1 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-β1 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-1β, TNF, 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-β1 in plasma and renal tissue. Renal Smad7 was up-regulated and both NF-B and TGF-β/Smad2/3 activation were suppressed. In conclusion, mice overexpressing latent TGF-β1 in the skin were protected against anti-GBM crescentic glomerulonephritis, possibly via Smad 7-mediated inhibition of NF-B-dependent renal inflammation and TGF-β/Smad2/3-dependent fibrosis.

This article has been cited by other articles:

				A. C. K. Chung, X. R. Huang, L. Zhou, R. Heuchel, K. N. Lai, and H. Y. Lan Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice Nephrol. Dial. Transplant., December 18, 2008; (2008) gfn699v1. [Abstract] [Full Text] [PDF]

				X. R. Huang, A. C. K. Chung, X. J. Wang, K. N. Lai, and H. Y. Lan Mice overexpressing latent TGF-{beta}1 are protected against renal fibrosis in obstructive kidney disease Am J Physiol Renal Physiol, July 1, 2008; 295(1): F118 - F127. [Abstract] [Full Text] [PDF]

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