Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery
Calcineurin is required in urinary tract mesenchyme for the development of the pyeloureteral peristaltic machinery
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DOI：
10.1172/jci200420049
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发表时间：
2004-04-01
影响因子：
15.9
通讯作者：
Chen, F
中科院分区：
文献类型：
--
作者：
Chang, CP;McDill, BW;Chen, F
先天性梗阻性肾病是婴幼儿肾功能衰竭的主要原因。然而，这种疾病的潜在分子和细胞机制在很大程度上仍然不确定。我们建立了一个类似于人类肾盂输尿管连接部梗阻的先天性梗阻性肾病小鼠模型。在这些小鼠中，通过使用Cre/lox系统选择性地删除发育中的尿路间充质中的Cnb1，钙调神经磷酸酶的功能被移除。这种缺失会导致发育中的尿路中的平滑肌细胞和其他间充质细胞的增殖减少。细胞增殖受损会导致肾盆和输尿管的异常发育，导致肾盂输尿管蠕动功能障碍，进行性肾梗阻，最终导致致命的肾功能衰竭。我们的研究表明，钙调神经磷酸酶是尿路发育过程中必不可少的信号分子，是尿路间充质细胞以细胞自主方式正常增殖所必需的。这些研究还强调了由发育异常引起的功能性梗阻在导致先天性梗阻性肾病中的重要性。
Congenital obstructive nephropathy is the principal cause of renal failure in infants and children. The underlying molecular and cellular mechanisms of this disease, however, remain largely undetermined. We generated a mouse model of congenital obstructive nephropathy that resembles ureteropelvic junction obstruction in humans. In these mice, calcineurin function is removed by the selective deletion of Cnb1 in the mesenchyme of the developing urinary tract using the Cre/lox system. This deletion results in reduced proliferation in the smooth muscle cells and other mesenchymal cells in the developing urinary tract. Compromised cell proliferation causes abnormal development of the renal pelvis and ureter, leading to defective pyeloureteral peristalsis, progressive renal obstruction, and, eventually, fatal renal failure. Our study demonstrates that calcineurin is an essential signaling molecule in urinary tract development and is required for normal proliferation of the urinary tract mesenchymal cells in a cell-autonomous manner. These studies also emphasize the importance of functional obstruction, resulting from developmental abnormality in causing congenital obstructive nephropathy.