title: Decoy receptor 3 inhibits renal mononuclear leukocyte infiltration and apoptosis and prevents progression of IgA nephropathy in mice.
abstract: The progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis, is associated with high levels of mononuclear leukocyte infiltration into the kidney. These cells consist mainly of T cells and macrophages. Our previous study showed that a decoy receptor 3 (DCR3) gene therapy can prevent the development of a mouse autoimmune glomerulonephritis model by its potent immune modulating effects (Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A. J Am Soc Nephrol 18: 2473-2485, 2007). Here, we tested the hypothesis that DCR3 might prevent the progression of IgAN, an immune complex-mediated primary glomerulonephritis, by inhibiting T cell activation, renal T cell/macrophage infiltration, and protecting the kidney from apoptosis. We used a progressive IgAN (Prg-IgAN) model in B cell-deficient mice, because the mice are characterized by a dramatic proliferation of activated T cells systemically and progressive NF-κB activation in the kidney. We treated the animals with short-term gene therapy with DCR3 plasmids by hydrodynamics-based gene delivery. When the mice were euthanized on day 21, we found that, compared with empty vector-treated (disease control) Prg-IgAN mice, DCR3 gene therapy resulted in 1) systemic inhibition of T cell activation and proliferation; 2) lower serum levels of proinflammatory cytokines; 3) improved proteinuria, renal function, and renal pathology (inhibiting the development of marked glomerular proliferation, crescent formation, glomerulosclerosis, and interstitial inflammation); 5) suppression of T cell and macrophage infiltration into the periglomerular interstitium of the kidney; and 5) a reduction in apoptotic figures in the kidney. On the basis of these findings, DCR3 might be useful therapeutically in preventing the progression of IgAN.
authors: Dept. of Pathology, Tri-Service General Hospital, National Defense Medical Center, No. 325 Sec. 2 Cheng-Gung Road, Taipei, Taiwan.
authors: Shuk-Man
authors: SM
authors: Ka
authors: Tai-Tzu
authors: TT
authors: Hsieh
authors: Shih-Hua
authors: SH
authors: Lin
authors: Sung-Sen
authors: SS
authors: Yang
authors: Chin-Chen
authors: CC
authors: Wu
authors: Huey-Kang
authors: HK
authors: Sytwu
authors: Ann
authors: A
authors: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D015316:Genetic Therapy; D005922:Glomerulonephritis, IGA / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007249:Inflammation / Q000097:blood; D007668:Kidney / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D051379:Mice; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000235:genetics*
chemical_list: D016207:Cytokines; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human