Oral administration of GW788388, an inhibitor of TGF-β type I and II receptor kinases, decreases renal fibrosis
Oral administration of GW788388, an inhibitor of TGF-β type I and II receptor kinases, decreases renal fibrosis
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DOI：
10.1038/sj.ki.5002717
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发表时间：
2008-03-01
影响因子：
19.6
通讯作者：
Laping, N. J.
中科院分区：
文献类型：
--
作者：
Petersen, M.;Thorikay, M.;Laping, N. J.
在多达三分之一的糖尿病患者中，进行性肾纤维化先于终末期肾功能衰竭。肾内转化生长因子-β(TGF-β)升高被认为是通过促进细胞外基质沉积和上皮-间充质转化而导致疾病进展的。GW788388是一种新型的转化生长因子-βI型受体抑制剂，与SB431542相比具有更好的药动学特征。我们在体外研究了它的作用，发现它既能抑制转化生长因子-βI型和II型受体的活性，但不能抑制相关的骨形态发生蛋白II型受体的活性。此外，它还阻止了转化生长因子-β诱导的Smad激活和靶基因表达，同时减少了上皮-间充质转化和纤维化形成。在发生糖尿病肾病的db/db小鼠身上，我们发现口服GW788388 5周显著减轻了肾脏纤维化，并降低了肾脏细胞外基质沉积的关键介质的mRNA水平。我们的研究表明，GW788388是一种有效的、选择性的体外转化生长因子-β信号转导和体内肾脏纤维化的抑制剂。
Progressive kidney fibrosis precedes end-stage renal failure in up to a third of patients with diabetes mellitus. Elevated intra-renal transforming growth factor-beta (TGF-beta) is thought to underlie disease progression by promoting deposition of extracellular matrix and epithelial-mesenchymal transition. GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542. We studied its effect in vitro and found that it inhibited both the TGF-beta type I and type II receptor kinase activities, but not that of the related bone morphogenic protein type II receptor. Further, it blocked TGF-beta-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis. Using db/db mice, which develop diabetic nephropathy, we found that GW788388 given orally for 5 weeks significantly reduced renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys. Our study shows that GW788388 is a potent and selective inhibitor of TGF-beta signalling in vitro and renal fibrosis in vivo.