Author(s): Fukasawa H, Yamamoto T, Suzuki H, Togawa A, Ohashi N,
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Abstract BACKGROUND: Although short-term treatment with anti-transforming growth factor-beta (TGF-beta) antibody (alphaT) has been shown to prevent early glomerular lesions, its long-term effects and molecular mechanisms, including intracellular signaling, remain poorly understood. We examined whether alphaT treatment induces prevention of renal insufficiency and fibrosis, and affects the TGF-beta/Smad signaling pathway in rats with chronic progressive anti-thymocyte serum (ATS) nephritis induced by repeated ATS injections on days 0 and 7. METHODS: Nephritic and non-nephritic rats were treated with either alphaT or control immunoglobulin (Ig)G twice weekly for 4 weeks from days 7 to 35 (each group, N= 21). Renal lesions and cortical expression of TGF-beta1, TGF-beta2, TGF-beta3, type II TGF-beta receptor (TbetaRII), Smads, type I collagen, and plasminogen activator inhibitor-1 were examined by immunohistochemistry, Western blot, and/or real-time reverse transcription polymerase chain reaction (RT-PCR). The binding of Smad3 in renal cortical cell nuclei to the Smad-binding element (SBE) was investigated by the electrophoretic mobility shift assay. RESULTS: Nephritic rats developed heavy proteinuria, renal insufficiency, and increased extracellular matrix deposition resulting in renal fibrosis. Cortical expression levels of TGF-beta1, TGF-beta2, TbetaRII, and Smad2, but not TGF-beta3, Smad3, and Smad4 were increased. Expression and preferential localization of phosphorylated Smad2/3 in the glomerular and tubular cell nuclei, and Smad3-SBE complex-forming activity were also increased. Four-week alphaT treatment resulted in marked amelioration of chronic progressive ATS nephritis at 8 weeks. CONCLUSION: In chronic progressive ATS nephritis, the TGF-beta/Smad signaling was up-regulated. TGF-beta blockade by alphaT suppressed the progression of renal scarring, at least in part, via inhibition of activated TGF-beta/Smad signaling.
This article was published in Kidney Int
and referenced in Journal of Diabetes & Metabolism