Smad7 Gene Therapy Ameliorates an Autoimmune Crescentic Glomerulonephritis in Mice

Abstract

Autoimmune crescentic glomerulonephritis is characterized by severe immune response with glomerular crescentic formation and fibrosis in the kidney. Recent studies indicate that overexpression of renal Smad7 attenuates both renal fibrosis and inflammation in rat remnant kidney. However, little attention has been paid to the potential role of TGF-␤/Smad signaling in autoimmune kidney disease. This study tested the hypothesis that blocking TGF-␤ signaling by overexpression of Smad7 may have a therapeutic effect in a mouse model of autoimmune crescentic glomerulonephritis that was induced in C57BL/6 ؋ DBA/2J F1 hybrid mice by giving DBA/2J donor lymphocytes. Smad7 gene was transfected into the kidney using the ultrasound-microbubble-mediated system. Results showed that overexpression of Smad7 blocked both renal fibrosis and inflammatory pathways in terms of Smad2/3 and NF-B activation (P < 0.01), thereby inhibiting ␣-smooth muscle actin; collagen I, III, and IV accumulation; and expression of inflammatory cytokines (IL-1␤ and IL-6), adhesion molecule/ chemokine (intercellular adhesion molecule-1, monocyte chemoattractant protein-1), and inducible nitric oxide synthase (all P < 0.01). Leukocyte infiltration (CD4 ؉ cells and macrophages) was also suppressed (P < 0.005). Severe histologic damage (glomerular crescent formation and tubulointerstitial injury) and functional injury including proteinuria were significantly improved (all P < 0.05). This study provides important evidence that overexpression of Smad7 may have therapeutic potential for autoimmune kidney disease.

Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy

“…12 Taken together, loss of Smad7 promotes, while overexpression of Smad7 inhibits, TGF-b/ Smad-mediated progressive renal fibrosis and NF-kB-driven renal inflammation as evidenced in a number of kidney disease models including UUO nephropathy, 12,37,40 hypertension-associated remnant kidney disease, 38,41 diabetic nephropathy, 14 and immunologically-mediated glomerulonephritis. 42 Therefore, loss of Ace2 promoted Ang II-induced Smurf2-dependent ubiquitin degradation of renal Smad7 may be another essential mechanism by which Ace2 À/y mice were promoted TGF-b/Smad-mediated renal fibrosis and NF-kB-driven renal inflammation in a mouse model of UUO nephropathy. Ace2 protects renal fibrosis and inflammation Z Liu et al…”

Functional and Structural Changes in End-Stage Kidney Disease due to Glomerulonephritis Induced by the Recombinant .ALPHA.3(IV)NC1 Domain

“…In support of our findings, recent studies have demonstrated that the expression of αSMA, type I collagen, and TGF-β increased in diseased kidneys and was accompanied by renal dysfunction, in other crescentic glomerulonephritis models induced by injection of anti-GBM antibody, and in models of Goodpasture's syndrome [3,16,17]. In addition, blocking of TGF-β signaling inhibited crescent formation and glomerulosclerosis, prevented the development of fibrosis and improved renal function in a model of autoimmune crescentic glomerulonephritis [10]. Therefore these fibrogenic factors may play an important role in the development and progression of renal failure.…”

Mechanisms of Tubulointerstitial Fibrosis

“…32,33 Activation of NF-B is critical for initiating the downstream release of PAI-1 or chemokines and growth factors, 196 particularly IL-1, 137 IL-6, 197 MCP-1/CCL2, 198,199 RAN-TES/CCL5, 113,200 or TNF␣. 200 In opposition, administration of Smad7, 201,202 paricalcitol, 203 truncated IB␣, 204 HGF, 200,205 spironolactone, 32,206 and decoy NF-B oligodeoxynucleotides 207 all attenuate tubulointerstitial injury by inhibiting the activity of NF-B. Experimental inhibition of proinflammatory chemokines such as TNF␣ or CCR1 has also been successful in preventing progressive interstitial injury.…”