Evidence for a role of transforming growth factor (TGF)-β1 in the induction of postglomerular albuminuria in diabetic nephropathy -: Amelioration by soluble TGF-β type II receptor
Evidence for a role of transforming growth factor (TGF)-β1 in the induction of postglomerular albuminuria in diabetic nephropathy -: Amelioration by soluble TGF-β type II receptor
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DOI：
10.2337/db06-1018
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发表时间：
2007-02-01
期刊：
影响因子：
7.7
通讯作者：
Lin, Herbert Y.
中科院分区：
文献类型：
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作者：
Russo, Leileata M.;del Re, Elisabetta;Lin, Herbert Y.
转化生长因子-β（TGF-β）先前已被牵连在糖尿病肾病的进展，包括纤维化和蛋白尿的发作。在这里，我们报告的第一次使用高亲和力的TGF-β 1结合分子，可溶性人TGF-β II型受体（sT β RII.Fc），在治疗糖尿病肾病12周链脲佐菌素诱导的糖尿病Sprague-Dawley大鼠。使用永生化大鼠近曲小管细胞的体外研究显示，50 pmol/l TGF-β 1破坏白蛋白摄取（与对照组相比P < 0.001），使用sT β RII.Fc（1，200 pmol/l）可显著逆转这种抑制作用。体内研究表明，用sT β RII.Fc治疗使尿白蛋白排泄在4周时减少36%，在8周时减少59%（P < 0.001），在12周时减少45%（糖尿病患者与治疗组相比P < 0.01）。这与sT β RII.Fc治疗后巨蛋白表达的增加（糖尿病患者与治疗组相比P < 0.05）和IV型胶原表达的减少（糖尿病患者与治疗组相比P < 0.001）相关。这些变化的发生与血糖水平的变化无关。本研究表明，sT β RII.Fc是治疗糖尿病肾病中纤维化和白蛋白尿的潜在新药，并可通过减少TGF-β 1诱导的肾近端小管细胞白蛋白摄取的破坏来减少白蛋白尿。
Transforming growth factor-beta (TGF-beta) has previously been implicated in the progression of diabetic nephropathy, including the onset of fibrosis and albuminuria. Here we report for the first time the use of a high-affinity TGF-beta 1 binding molecule, the soluble human TGF-beta type II receptor (sT beta RII.Fc), in the treatment of diabetic nephropathy in 12-week streptozotocin-induced diabetic Sprague-Dawley rats. In vitro studies using immortalized rat proximal tubule cells revealed that 50 pmol/l TGF-beta 1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sT beta RII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sT beta RII.Fc reduced urinary albumin excretion by 36% at 4 weeks, 59% at 8 weeks (P < 0.001), and 45% at 12 weeks (P < 0.01 for diabetic vs. treated). This was correlated with an increase in megalin expression (P < 0.05 for diabetic vs. treated) and a reduction in collagen IV expression follow ing sT beta RII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sT beta RII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-beta 1-induced disruptions of renal proximal tubule cell uptake of albumin.