Kim Sung Il, Lee So-Young, Wang Zhibo, Ding Yan, Haque Nadeem, Zhang Jiwang, Zhou Jing, Choi Mary E
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Division of Nephrology and Hypertension, Weill Cornell Medical College, New York, New York;
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Internal Medicine, Bundang CHA Medical Center, CHA University School of Medicine, Seongnam, South Korea; and.
J Am Soc Nephrol. 2014 Sep;25(9):1966-78. doi: 10.1681/ASN.2013030252. Epub 2014 Mar 20.
TGF-β-activated kinase 1 (TAK1) is a key intermediate in signal transduction induced by TGF-β or inflammatory cytokines, such as TNF-α and IL-1, which are potent inducers of podocyte injury responses that lead to proteinuria and glomerulosclerosis. Nevertheless, little is known about the physiologic and pathologic roles of TAK1 in podocytes. To examine the in vivo role of TAK1, we generated podocyte-specific Tak1 knockout mice (Nphs2-Cre(+):Tak1(fx/fx); Tak1(∆/∆)). Targeted deletion of Tak1 in podocytes resulted in perinatal lethality, with approximately 50% of animals dying soon after birth and 90% of animals dying within 1 week of birth. Tak1(∆/∆) mice developed proteinuria from P1 and exhibited delayed glomerulogenesis and reduced expression of Wilms' tumor suppressor 1 and nephrin in podocytes. Compared with Tak1(fx/fx) mice, Tak1(∆/∆) mice exhibited impaired formation of podocyte foot processes that caused disruption of the podocyte architecture with prominent foot process effacement. Intriguingly, Tak1(∆/∆) mice displayed increased expression of vascular endothelial growth factor within the glomerulus and abnormally enlarged glomerular capillaries. Furthermore, 4- and 7-week-old Tak1(∆/∆) mice with proteinuria had increased collagen deposition in the mesangium and the adjacent tubulointerstitial area. Thus, loss of Tak1 in podocytes is associated with the development of proteinuria and glomerulosclerosis. Taken together, our data show that TAK1 regulates the expression of Wilms' tumor suppressor 1, nephrin, and vascular endothelial growth factor and that TAK1 signaling has a crucial role in podocyte differentiation and attainment of normal glomerular microvasculature during kidney development and glomerular filtration barrier homeostasis.
转化生长因子-β激活激酶1（TAK1）是由转化生长因子-β或炎性细胞因子（如肿瘤坏死因子-α和白细胞介素-1）诱导的信号转导中的关键中间体，这些细胞因子是足细胞损伤反应的强效诱导剂，可导致蛋白尿和肾小球硬化。然而，关于TAK1在足细胞中的生理和病理作用知之甚少。为了研究TAK1在体内的作用，我们构建了足细胞特异性Tak1基因敲除小鼠（Nphs2-Cre(+)：Tak1(fx/fx)；Tak1(∆/∆)）。足细胞中Tak1的靶向缺失导致围产期致死率，约50%的动物在出生后不久死亡，90%的动物在出生后1周内死亡。Tak1(∆/∆)小鼠从出生后第1天开始出现蛋白尿，表现出肾小球生成延迟，足细胞中肾母细胞瘤抑制因子1和nephrin的表达降低。与Tak1(fx/fx)小鼠相比，Tak1(∆/∆)小鼠足细胞足突的形成受损，导致足细胞结构破坏，足突明显消失。有趣的是，Tak1(∆/∆)小鼠肾小球内血管内皮生长因子的表达增加，肾小球毛细血管异常增大。此外，4周龄和7周龄有蛋白尿的Tak1(∆/∆)小鼠系膜和相邻肾小管间质区域的胶原沉积增加。因此，足细胞中Tak1的缺失与蛋白尿和肾小球硬化的发生有关。综上所述，我们的数据表明TAK1调节肾母细胞瘤抑制因子1、nephrin和血管内皮生长因子的表达，并且TAK1信号在肾脏发育和肾小球滤过屏障稳态过程中足细胞分化和正常肾小球微血管的形成中起关键作用。
