Chronic Allograft Nephropathy: Intraepithelial Signals Generated by Transforming Growth Factor‐β and Bone Morphogenetic Protein‐7
Chronic Allograft Nephropathy: Intraepithelial Signals Generated by Transforming Growth Factor‐β and Bone Morphogenetic Protein‐7
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慢性同种异体移植肾病：转化生长因子-β 和骨形态发生蛋白-7 产生的上皮内信号
DOI：
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发表时间：
2006
影响因子：
8.8
通讯作者：
John A. Kirby
中科院分区：
文献类型：
--
作者：
J. Tyler;H. Robertson;T. Booth;Alastair D. Burt;John A. Kirby
已有研究表明，转化生长因子β可通过诱导上皮细胞向间充质细胞转化而导致慢性移植物肾病，而骨形态发生蛋白-7(BMP7)可引起一种逆转转化。目前的研究评估了转化生长因子β和骨形态发生蛋白7在正常肾脏和移植后肾小管上皮细胞内产生的信号的相对贡献。正常人肾上皮细胞在细胞核内表达Smad2/3和Smad1/5/8的磷酸化形式；细胞培养实验表明，这些信号分子分别是对转化生长因子β和骨形态发生蛋白7的反应而产生的。在急性肾移植排斥反应和慢性移植肾肾病过程中，肾小管上皮细胞磷酸化(P)-Smad2/3的表达水平升高，而pSmad1/5/8的表达水平很低；这种染色图谱与EMT标记物S100A4的诱导有关。进一步的体外实验证明，这种Smad信号模式是在缺乏骨形态发生蛋白7的情况下，转化生长因子β刺激肾小管上皮细胞的结果。重要的是，在转化生长因子β刺激的细胞中加入骨形态发生蛋白7可增强pSmad1/5/8的表达，降低S100A4的表达。这些结果表明，外源性BMP7可以恢复正常肾脏中pSmad信号的动态平衡，从而预防或逆转慢性移植物肾病的发展。
It has been suggested that TGFβ can cause chronic allograft nephropathy by inducing epithelial to mesenchymal transition (EMT); some studies show a reverse transition can be produced by bone morphogenetic protein‐7 (BMP7). The current study assessed the relative contribution of signals generated within tubular epithelial cells by TGFβ and BMP7 in normal kidney and after transplantation. Epithelial cells in normal human kidneys expressed phosphorylated forms of both Smad2/3 and Smad1/5/8 within their nuclei; cell culture experiments showed that these signaling molecules were generated in response to TGFβ and BMP7, respectively. Phospho(p)‐Smad2/3 was expressed at increased levels by tubular epithelial cells during acute renal allograft rejection and chronic allograft nephropathy but pSmad1/5/8 was expressed at very low levels; this staining profile was associated with induction of the EMT marker, S100A4. Further in vitro experiments demonstrated that this pattern of Smad signaling was a consequence of the stimulation of tubular epithelial cells with TGFβ in the absence of BMP7. Importantly, addition of BMP7 to TGFβ‐stimulated cells enhanced the expression of pSmad1/5/8 and reduced expression of S100A4. These results suggest that exogenous BMP7 could restore the homeostatic balance of pSmad signaling found in normal kidneys, thereby preventing or reversing the development of chronic allograft nephropathy.
DOI：
10.1172/jci20530
发表时间：
2003-12
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
R. Kalluri;E. Neilson
通讯作者：
R. Kalluri;E. Neilson
影响因子：
6.2
作者：
Hadley, GA;Rostapshova, EA;Weir, MR
通讯作者：
Weir, MR
影响因子：
19.6
作者：
Strutz, F;Zeisberg, M;Sisic, Z
通讯作者：
Sisic, Z