Barasch J, Yang J, Qiao J, Tempst P, Erdjument-Bromage H, Leung W, Oliver J A
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
J Clin Invest. 1999 May;103(9):1299-307. doi: 10.1172/JCI4586.
Development of the embryonic kidney results from reciprocal signaling between the ureteric bud and the metanephric mesenchyme. To identify the signaling molecules, we developed an assay in which metanephric mesenchymes are rescued from apoptosis by factors secreted from ureteric bud cells (UB cells). Purification and sequencing of one such factor identified the tissue inhibitor of metalloproteinase-2 (TIMP-2) as a metanephric mesenchymal growth factor. Growth activity was unlikely due to TIMP-2 inhibition of matrix metalloproteinases because ilomastat, a synthetic inhibitor of these enzymes, had no mesenchymal growth action. TIMP-2 was also involved in morphogenesis of the ureteric bud, inhibiting its branching and changing the deposition of its basement membrane; these effects were due to TIMP-2 inhibition of matrix metalloproteinases, as they were reproduced by ilomastat. Thus, TIMP-2 regulates kidney development by at least 2 distinct mechanisms. In addition, TIMP-2 was secreted from UB cells by mesenchymal factors that are essential for ureteric bud development. Hence, the mesenchyme synchronizes its own growth with ureteric morphogenesis by stimulating the secretion of TIMP-2 from the ureteric bud.
胚胎肾的发育源于输尿管芽和后肾间充质之间的相互信号传导。为了鉴定信号分子，我们开发了一种检测方法，即通过输尿管芽细胞（UB细胞）分泌的因子拯救后肾间充质免于凋亡。对其中一种因子进行纯化和测序后，确定金属蛋白酶组织抑制剂-2（TIMP-2）为后肾间充质生长因子。其生长活性不太可能是由于TIMP-2对基质金属蛋白酶的抑制作用，因为这些酶的合成抑制剂伊洛马司他没有间充质生长作用。TIMP-2还参与输尿管芽的形态发生，抑制其分支并改变其基底膜的沉积；这些作用是由于TIMP-2对基质金属蛋白酶的抑制作用，因为伊洛马司他可重现这些作用。因此，TIMP-2通过至少两种不同机制调节肾脏发育。此外，TIMP-2由UB细胞通过对输尿管芽发育至关重要的间充质因子分泌。因此，间充质通过刺激输尿管芽分泌TIMP-2来使其自身生长与输尿管形态发生同步。
