Latent TGF- 1 Protects Against Crescentic Glomerulonephritis

Despite the critical role that TGFplays in renal fibrosis, transgenic mice that overexpress human latent TGF1 in the skin exhibit normal renal histology and function even though circulating levels of latent TGF1 are an order of magnitude higher than wild-type animals. In fact, latent TGF1 seems to protect against renal inflammation in a model of ureteral obstruction. It is unknown, however, whether latent TGF1 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 TGF1 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-1 , 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, TGF1 in plasma and renal tissue. Renal Smad7 was up-regulated and both NFB and TGF/Smad2/3 activation were suppressed. In conclusion, mice overexpressing latent TGF1 in the skin were protected against anti-GBM crescentic glomerulonephritis, possibly via Smad 7-mediated inhibition of NFB-dependent renal inflammation and TGF/Smad2/3-dependent fibrosis. J Am Soc Nephrol 19: 233–242, 2008. doi: 10.1681/ASN.2007040484 TGF1 exhibits a broad spectrum of biological functions in inflammation, immune response, and tissue repair/ fibrosis.1,2 Although TGF1 play a critical role in renal fibrosis,3 little attention has been paid to the potential role of this cytokine in inflammatory and immune-mediated kidney diseases. TGFis an anti-inflammatory cytokine and functions in both autocrine and paracrine manners to regulate cell proliferation, apoptosis, chemotaxis, immunity, and inflammatory response.1,2 This is illustrated by the finding that mice with targeted disruption of TGF1 develop a wasting syndrome associated with multifocal inflammation at about 3 wk after birth.4 In addition, systemic administration or overexpression of TGFproduces an inhibitory effect on erosive arthritis,5 autoimmune encephalomyelitis,6 insulitis in nonobese diabetic mice,7 and systemic lupus erythematosus in the MRL/lpr/lpr mice.8 These findings provide strong evidence for the anti-inflammatory properties of TGFin the disease conditions. It has been shown that mice with overexpression of active TGF1 in the liver develop severe renal damage with progressive renal fibrosis.9 In contrast, we have recently found that TGF1 Tg mice overexReceived April 20, 2007. Accepted August 9, 2007. Published online ahead of print. Publication date available at www.jasn.org. 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: [email protected] Copyright © 2008 by the American Society of Nephrology BASIC RESEARCH www.jasn.org J Am Soc Nephrol 19: 233–242, 2008 ISSN : 1046-6673/1902-233 233 pressing a human Wt-TGF1 in the skin exhibit a normal renal histology and function without detectable kidney abnormalities, despite a ten-fold increase in circulating levels of latent TGF1.10 Moreover, we also found that mice with elevated levels of a latent form of TGF1 in plasma and renal tissues are able to prevent renal inflammation in a mouse model of obstructive kidney.10 These contradictory findings suggest a complex role of TGF1 in renal pathophysiological conditions. Although it is known that mice overexpressing latent TGF1 can prevent renal inflammation in a model of obstructive kidney induced by ureteral ligation,10 it remains unclear whether latent TGF1 is able to protect against renal injury under the immunological condition. To address this question, we examined the functional role of TGF1 in an immunologically induced kidney disease induced in TGF1 Tg mice by administrating the sheep anti-mouse glomerular basement membrane (GBM) antibody. In this model, a severe and rapidly progressive crescentic GN was developed and the protective role of TGF1 in immune-mediated kidney disease was investigated.