Latent TGF-β1 Protects Against Crescentic Glomerulonephritis

Abstract

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

Chemokines in Renal Injury

“…7,15 Activation of TGF␤/Smad2,3 signaling during renal inflammation also produces a chemotatic effect on macrophages by inducing monocyte chemoattractant protein-1 (MCP-1)/ CCL2 expression. 16,17 Furthermore, urinary levels of TWEAK, a cytokine of the TNF superfamily, significantly increase and correlate with the activity of renal disease in patients with active lupus nephritis. 18 Exposure to TWEAK also induces MCP-1/CCL2, RANTES/CCL5, MIP-1␣/CXCL2, intraperitoneally-10/CXCL10, and SLC/CCL21 in MCs or tubular epithelial cells through a noncanonical NF-B pathway, thereby promoting leukocyte recruitment to the kidney during injury.…”

“…55,61,9 In unilateral ureteral obstruction (UUO) producing fibrosis, upregulation of tubulointerstitial MCP-1/ CCL2 correlates with degree of macrophage infiltration, which is associated with activation of the TGF␤/Smad3 signaling pathway. 16,17 TGF␤ signals through its downstream mediator, Smad3, to induce MCP-1 expression. Thus, mice deficient in Smad7, an inhibitor of TGF␤/Smad signaling, results inenhancedTGF␤/Smad3signalingthrough which MCP-1/CCL2-dependent macrophage infiltration and tubulointerstitial fibrosis develop in the UUO kidney.…”

“…16 In contrast, inhibition or loss of TGF␤/Smad3 signalingblocksMCP-1expressionandmac-rophage accumulation in anti-GBM nephritis and UUO. 17,[62][63][64][65] Thus, upregulation of MCP-1/CCL2 and the development of macrophage accumulation in chronic kidney disease may be TGF␤/Smad3-dependent.…”

Efficacy of antisense monocyte chemoattractant protein-1 (MCP-1) in a rat model of mesangial proliferative glomerulonephritis

“…37 If the inflammation persists, excessive secretion of TGF-b 1 may reduce the inflammatory response by inhibiting the production of a variety of proinflammatory cytokines and chemokines. [38][39][40] In conclusion, the present study demonstrated that: (1) antisense MCP-1 can inhibit the expression of MCP-1, but cannot reduce the expression of TGF-b 1 , which may be due to the bidirectional regulatory effect of TGF-b 1 ; and (2) antisense MCP-1 suppressed mesangial cell proliferation and mesangial matrix accumulation in anti-Thy1 MsPGN model rats, which did not entirely depend on the role of TGFb 1 and may involve other mechanisms. Therefore, our data indicate that antisense MCP-1 may be a potent therapeutic target for the treatment of MsPGN.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…102,103 The overexpression of TGF-b-binding peptide, which keeps TGF-b in its latent form, has also been shown to inhibit tissue fibrosis. 104,105 This evidence indicates that blocking the TGF-b signaling pathway may be an essential therapy for tissue fibrosis.…”