Tubular expression of heat-shock protein 27 inhibits fibrogenesis in obstructive nephropathy.
Tubular expression of heat-shock protein 27 inhibits fibrogenesis in obstructive nephropathy.
复制标题
DOI：
10.1038/ki.2012.336
复制
发表时间：
2013-01
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
肾损伤时发生的形态学变化涉及肌动蛋白骨架重塑。在这里，我们测试了热休克蛋白27（HSP 27），一种参与细胞骨架重塑的小的应激反应蛋白，是否保护肾脏免受阻塞性肾病肾小管间质纤维化的影响。肾盂输尿管连接部梗阻患者肾小管细胞HSP 27免疫染色显著增加，支持我们研究的临床意义。为了建立一种机制研究的动物模型，我们在肾雄激素调节蛋白启动子下产生了在肾小管中特异性过表达人HSP 27的转基因小鼠，并确定了HSP 27过表达对单侧输尿管梗阻后上皮-间质转化和肾小管间质纤维化的影响。这与纤维形成减少有关，如磷酸化p38 MAPK、胶原III、α-平滑肌肌动蛋白、4-羟基壬烯醛的显著下降和梗阻后三色染色减少所证明的。值得注意的是，E-钙粘蛋白和β-连环蛋白保留在输尿管梗阻的转基因小鼠的肾小管细胞的细胞膜上。然而，在这些转基因小鼠中，单核细胞/巨噬细胞浸润没有受到显著影响。因此，肾小管HSP 27抑制阻塞性肾病的纤维化。HSP 27与E-cadherin-β-catenin复合物相互作用的调控途径有待进一步研究。
Morphological changes that occur during kidney injury involve actin skeleton remodeling. Here we tested whether heat shock protein 27 (HSP27), a small stress response protein involved in cytoskeletal remodeling, protects the kidney from tubulointerstitial fibrosis in obstructive nephropathy. Tubular cell HSP27 immunostaining was significantly increased in human kidneys with ureteropelvic junction obstruction; supporting the clinical relevance of our studies. To develop an animal model for mechanistic studies we generated transgenic mice that specifically overexpress human HSP27 in renal tubules, under the kidney androgen-regulated protein promoter, and determined the effects of HSP27 overexpression on epithelial-to-mesenchymal transition and tubulointerstitial fibrosis following unilateral ureteral obstruction. This was associated with decreased fibrogenesis as evidenced by significant declines in phosphorylated p38MAPK, collagen III, α-smooth muscle actin, 4-hydroxynonenal, and reduced trichrome staining following obstruction. Notably, E-cadherin and β-catenin remained at the cell membrane of tubular cells in transgenic mice with an obstructed ureter. Monocyte/macrophage infiltration, however, was not significantly affected in these transgenic mice. Thus, tubular HSP27 inhibits fibrogenesis in obstructive nephropathy. Further studies are needed to determine pathways regulating the interactions between HSP27 and the E-cadherin-β-catenin complex.
登录
查看更多内容
DOI：
10.1111/j.1600-6143.2012.04081.x
发表时间：
2012-08
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Djamali A;Reese S;Hafez O;Vidyasagar A;Jacobson L;Swain W;Kolehmainen C;Huang L;Wilson NA;Torrealba JR
通讯作者：
Torrealba JR
影响因子：
5.3
作者：
LAVOIE, JN;LAMBERT, H;LANDRY, J
通讯作者：
LANDRY, J
影响因子：
3.7
作者：
Levenson, Richard M.
通讯作者：
Levenson, Richard M.
影响因子：
4.8
作者：
Berkowitz, P;Hu, PQ;Rubenstein, DS
通讯作者：
Rubenstein, DS
影响因子：
4.8
作者：
Rogalla, T;Ehrnsperger, M;Gaestel, M
通讯作者：
Gaestel, M