Glucocorticoid regulation of proteoglycan synthesis in mesangial cells
Glucocorticoid regulation of proteoglycan synthesis in mesangial cells
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DOI：
10.1046/j.1523-1755.2002.00524.x
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发表时间：
2002-09-01
影响因子：
19.6
通讯作者：
Saruta, T
中科院分区：
文献类型：
--
作者：
Kuroda, M;Sasamura, H;Saruta, T
背景蛋白聚糖是肾小球系膜基质和肾小球通透性屏障的组成部分。最近的研究表明，肾小球蛋白多糖表达的变化可能在肾脏疾病的发病机制中发挥重要作用。类固醇激素是治疗肾小球疾病的首选药物，但糖皮质激素对肾小球蛋白多糖表达的影响尚不清楚。本研究采用大鼠（RMC）和人（HMC）系膜细胞，检测了地塞米松在体外和体内给药对蛋白多糖合成和蛋白多糖核心蛋白基因表达的影响。用地塞米松处理培养的RMC导致细胞相关和分泌的蛋白聚糖合成的剂量和时间依赖性降低（P < 0.05）至对照水平的约50%。这种作用被糖皮质激素拮抗剂米非司酮所抑制，并被泼尼松龙或皮质酮治疗所模仿。通过离子交换和凝胶渗透色谱法分离的蛋白多糖表明，硫酸软骨素/硫酸皮肤素蛋白多糖下调类固醇治疗后。北方印迹分析、RT-PCR、Western印迹和启动子活性测定揭示地塞米松引起核心蛋白聚糖mRNA的显著降低（至对照的61 ± 8%），而双糖链蛋白聚糖表达和启动子活性在类固醇处理后增加。在从体内用地塞米松处理的大鼠分离的肾小球中发现了类似的趋势。这些结果表明，治疗系膜细胞与类固醇的结果在减少总蛋白多糖的合成，以及亚型特异性的蛋白多糖核心蛋白基因表达的转录控制的变化，进一步了解类固醇治疗对肾小球的影响。
Background. Proteoglycans are integral components of the mesangial matrix and glomerular permeability barrier. Recent studies have shown that changes in glomerular proteoglycan expression may play a major role in the pathogenesis of renal disease. Steroid hormones are used as first-choice therapy for the treatment of glomerular diseases, however, the effects of glucocorticoids on expression of glomerular proteoglycans are unknown.Methods. This study examined the effects of in vitro and in vivo administration of dexamethasone on proteoglycan synthesis and gene expression of proteoglycan core proteins using rat (RMC) and human (HMC) mesangial cells.Results. Treatment of cultured RMC with dexamethasone resulted in a dose- and time-dependent decrease (P < 0.05) in both cell-associated and secreted proteoglycan synthesis to approximately 50% of control levels. This effect was inhibited by the glucocorticoid antagonist mifepristone, and mimicked by prednisolone or corticosterone treatment. Separation of proteoglycans by ion-exchange and gel permeation chromatography suggested that chondrotin sulfate/dermatan sulfate proteoglycans were down-regulated after steroid treatment. Northern blot analysis, RT-PCR, Western blot, and promoter activity assays revealed that dexamethasone caused a significant decrease in decorin mRNA (to 61 ± 8% of controls), whereas biglycan expression and promoter activity were increased after steroid treatment. A similar trend was found in glomeruli isolated from rats treated in vivo with dexametbasone.Conclusions. These results demonstrate that treatment of mesangial cells with steroids results in a decrease in total proteoglycan synthesis, as well as subtype-specific changes in proteoglycan core protein gene expression by transcriptional control, furthering our understanding of the effects of steroid treatment on the renal glomeruli.