ELEVATED EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA AND PROTEOGLYCAN PRODUCTION IN EXPERIMENTAL GLOMERULONEPHRITIS - POSSIBLE ROLE IN EXPANSION OF THE MESANGIAL EXTRACELLULAR-MATRIX
ELEVATED EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA AND PROTEOGLYCAN PRODUCTION IN EXPERIMENTAL GLOMERULONEPHRITIS - POSSIBLE ROLE IN EXPANSION OF THE MESANGIAL EXTRACELLULAR-MATRIX
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DOI：
10.1172/jci114731
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发表时间：
1990-08-01
影响因子：
15.9
通讯作者：
BORDER, WA
中科院分区：
文献类型：
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作者：
OKUDA, S;LANGUINO, LR;BORDER, WA
肾小球细胞外基质积聚是进行性肾小球肾炎的显著特征。之前，我们已经证明了转化生长因子。（TGF-. β）在体外调节肾小球系膜细胞产生蛋白聚糖biglycan和decorin方面是生长因子中独特的。我们现在提供了TGF- β表达升高的证据。抗胸腺细胞血清（ATS）对大鼠肾小球肾炎的影响。在给药后1、4、7、14和28 d从大鼠肾脏中培养肾小球。从第4天开始检测到蛋白多糖合成增加，在第7天达到峰值，与对照组相比增加了4,900%，并在第28天恢复到对照水平。通过加入抗TGF- β合成肽的抗血清，可大大降低培养的肾小球蛋白多糖合成的增加以及纤维连接蛋白的合成。来自ATS肾小球培养物的条件培养基，当加入到正常培养的系膜细胞中时，诱导蛋白多糖合成升高，也在第7天达到峰值，这与添加外源性TGF-. β的反应相似。加入TGF- β阻断条件介质的刺激活性。抗血清。事先在抗血清中加入免疫肽可消除阻断作用。用免疫沉淀法鉴定了主要的诱导蛋白多糖为biglycan和decorin。肾小球组织学显示系膜基质扩张的时间过程大致与ATS肾小球蛋白多糖合成的升高和这些肾小球条件介质诱导蛋白多糖合成的能力相一致。同时TGF-. β表达升高。mRNA和TGF- β。肾小球中的蛋白质。这些结果表明TGF- β具有核心作用。病理性细胞外基质在肾小球肾炎中的积累。
Glomerular accumulation of extracellular matrix is a prominent feature of progressive glomerulonephritis. Previously, we have shown that transforming growth factor-.beta. (TGF-.beta.) is unique among growth factors in regulating the production of the proteoglycans biglycan and decorin by glomerular mesangial cells in vitro. We now provide evidence of an elevated expression of TGF-.beta., proteoglycans, and fibronectin in glomerulonephritis induced in rats by injection of anti-thymocyte serum (ATS). Glomeruli were cultured from rat kidneys at 1, 4, 7, 14, and 28 d after ATS administration. Increased proteoglycan synthesis was detected beginning on day 4, which peaked at a 4,900% increase compared with control on day 7, and returned toward control levels by day 28. The increased proteoglycan synthesis by cultured nephritic glomeruli, as well as that of fibronectin, were greatly reduced by addition of antiserum raised against a synthetic peptide from TGF-.beta.. Conditioned media from ATS glomerular cultures, when added to normal cultured mesangial cells, induced elevated proteoglycan synthesis that also peaked on day 7 and that mimicked the response to added exogenous TGF-.beta.. The stimulatory activity of the conditioned media was blocked by addition of TGF-.beta. antiserum. Prior addition of the immunizing peptide to the antiserum abolished the blocking effect. The main induced proteoglycans were identified as biglycan and decorin by immunoprecipitation with antiserum made against synthetic peptides from the proteoglycan core proteins. Glomerular histology showed mesangial matrix expansion in a time course that roughly paralleled both the elevated proteoglycan synthesis by the ATS glomeruli and the ability of the conditioned media from these glomeruli to induce proteoglycan synthesis. At the same time there was an increased expression of TGF-.beta. mRNA and TGF-.beta. protein in the glomeruli. These results suggest a central role for TGF-.beta. in the accumulation of pathological extracellular matrix in glomerulonephritis.