C-peptide reverses TGF-β1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy
C-peptide reverses TGF-β1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy
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DOI：
10.1152/ajprenal.90500.2008
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发表时间：
2009-03-01
影响因子：
4.2
通讯作者：
Brunskill, Nigel J.
中科院分区：
文献类型：
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作者：
Hills, Claire E.;Al-Rasheed, Nawal;Brunskill, Nigel J.
Hills CE，Al-Rasheed N，Al-Rasheed N，Willars GB，Brunskill NJ。C-肽逆转转化生长因子-β1诱导的肾近端小管细胞改变：对糖尿病肾病治疗的启示。Am J Physiol Renal Physiol 296：F614-F621,2009。2008年12月17日首次出版；DOI：10.1152/ajprenal.90500.2008。-糖尿病进行性慢性肾脏疾病背后的关键病理是肾小管间质纤维化。这一过程的中心是近端肾小管上皮细胞的上皮-间充质转化(EMT)，由不适应的转化生长因子-β1(TGF-β1)信号驱动。最近发现了C-肽的新的信号作用，有证据表明C-肽可以减轻糖尿病的微血管并发症。我们研究了C-肽在HK2人肾小管上皮细胞中阻断损伤的转化生长因子-β1信号通路，从而阻断肾小管上皮细胞转化的可能性。细胞与转化生长因子-β1单独孵育或与C-肽在低糖或高糖中孵育。观察细胞形态、转化生长因子-β1受体表达、波形蛋白、E-钙粘蛋白和磷酸化Smads的变化。荧光素酶记者用来评估Smad的活性。TRITC-鬼臼蛋白染色显示细胞骨架。C肽治疗可阻止转化生长因子-β1刺激的、EMT相关的近端肾小管细胞典型的形态改变，包括波形蛋白表达增加、E-钙粘蛋白表达降低和细胞骨架重排。C-肽还可阻断转化生长因子-β1诱导的I型和II型转化生长因子-β1受体的表达上调，并减弱转化生长因子-β1介导的Smad磷酸化和Smad转录活性。百日咳毒素可抑制C-肽的上述作用。结果表明，C-肽几乎完全逆转了转化生长因子-β1诱导的PT细胞的形态变化，提示C-肽在糖尿病肾病中具有肾脏保护作用。
Hills CE, Al-Rasheed N, Al-Rasheed N, Willars GB, Brunskill NJ. C-peptide reverses TGF-beta 1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy. Am J Physiol Renal Physiol 296: F614-F621, 2009. First published December 17, 2008; doi:10.1152/ajprenal.90500.2008.-The crucial pathology underlying progressive chronic kidney disease in diabetes is tubulointerstitial fibrosis. Central to this process is epithelial-mesenchymal transformation (EMT) of proximal tubular epithelial cells driven by maladaptive transforming growth factor-beta 1 (TGF-beta 1) signaling. Novel signaling roles for C-peptide have recently been discovered with evidence emerging that C-peptide may mitigate microvascular complications of diabetes. We studied the potential for C-peptide to interrupt injurious TGF-beta 1 signaling pathways and thus block development of EMT in HK2 human kidney proximal tubular cells. Cells were incubated with TGF-beta 1 either alone or with C-peptide in low or high glucose. Changes in cell morphology, TGF-beta 1 receptor expression, vimentin, E-cadherin, and phosphorylated Smads were assessed. Luciferase reporters were used to assess Smad activity. The cytoskeleton was visualized by TRITC-phalloidin staining. The typical TGF-beta 1-stimulated, EMT-associated morphological alterations of proximal tubular cells, including increased vimentin expression, decreased E-cadherin expression, and cytoskeletal rearrangements, were prevented by C-peptide treatment. C-peptide also blocked TGF-beta 1-induced upregulation of expression of both type I and type II TGF-beta 1 receptors and attenuated TGF-beta 1-mediated Smad phosphorylation and Smad transcriptional activity. These effects of c-peptide were inhibited by pertussis toxin. The results demonstrate that C-peptide almost completely reversed the morphological changes in PT cells induced by TGF-beta 1 and suggest a role or c-peptide as a renoprotective agent in diabetic nephropathy.