Effects of All-Trans-Retinoic Acid (atRA) on Inducible Nitric Oxide Synthase (iNOS) Activity and Transforming Growth Factor Beta-1 Production in Experimental Anti-GBM Antibody-Mediated Glomerulonephri

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• 作者：Datta ; Prasun K. ; Reddy ; R. Sreenivas ; Lianos ; Elias A.
• 关键词：All ; Trans ; Retinoic Acid (atRa) ; Inducible Nitric Oxide Synthase (iNOS) ; Transforming Growth Factor Beta ; 1 ; Anti ; GBM Antibody ; Medated Glomerulonephritis
• 刊名：Inflammation
• 出版年：2001
• 出版时间：2001
• 年：2001
• 卷：25
• 期：6
• 页码：351-359
• 全文大小：413 KB

文摘

Sustained high output release of Nitric oxide (NO) as result of activation of inducible nitric oxide synthase (iNOS), and increased production of the antiproliferative/profibrotic cytokine transforming growth factor-β1 (TGF-β1) are well documented in glomerulonephritis. Modulation of iNOS activity and of TGF-β1 production can therefore be viewed as anti-inflammatory strategies. The present study employed all-trans retinoic acid (atRA) which is known to have anti-inflammatory effects and to modulate expression of iNOS and TGF-β1, in order to explore its effect on iNOS enzyme activity and TGF-β1 production in anti-GBM antibody induced glomerulonephritis. Glomerulonephritis was induced in Lewis rats by injection of anti-GBM antibody. A group of nephritic rats were given daily administration of atRA for 14–16 days. Extent of proteinuria was assessed by measuring urine protein and creatinine excretion. iNOS enzyme activity was measured by calculating conversion of L[$^14$C]arginine to L-[$^14$C]citrulline in glomerular protein lysates. Levels of TGF-β1 in glomerular protein lysates were measured by quantitative ELISA. Levels of proliferating nuclear antigen (PCNA), TGF-β receptor II (TGFβ-RII), and fibronectin were assessed by Western blot analysis. Glomerular iNOS activity in atRA treated nephritic animals was attenuated in comparison to that in nephritic controls that were not. Glomerular expression of PCNA was also reduced. Levels of TGF-β1 were increased in glomeruli of atRA treated nephritic animals. In these animals, there was no change in glomerular levels of TGF-β receptor II (TGFβ-RII) or fibronectin, and there was no reduction in urine protein excretion. These results suggest that atRA attenuates iNOS activity and proliferation in glomeruli of nephritic animals. The failure of atRA treatment to reduce proteinuria could be due to the increase in TGF-β1 levels and to inhibition of iNOS-driven NO production.