Gupta Deepak Prasad, Hwang Jae-Won, Cho Eui-Sic, Kim Won, Song Chang Ho, Chai Ok Hee
Department of Anatomy, Chonbuk National University Medical School and Institute for Medical Sciences, Chonbuk National University, Jeonju, Republic of Korea.
Cells Tissues Organs. 2017;204(1):38-48. doi: 10.1159/000464460. Epub 2017 Jun 1.
Sonic Hedgehog (Shh) signaling plays a major role in and is essential for regulation, patterning, and proliferation during renal development. Smoothened (Smo) plays a pivot role in transducing the Shh-glioma-associated oncogene Kruppel family member. However, the cellular and molecular mechanism underlying the role of sustained Smo activation in postnatal kidney development is still not clearly understood. Using a conditional knockin mouse model that expresses a constitutively activated form of Smo (SmoM2) upon Homeobox-B7-mediated recombination (Hoxb7-Cre), the effects of Shh signaling were determined in postnatal kidney development. SmoM2;Hoxb7-Cre mutant mice showed growth retardation with a reduction of body weight. Constitutive activation of Smo in the renal collecting ducts caused renal hypoplasia, hydronephrosis, and hydroureter. The parenchymal area and glomerular numbers were reduced, but the glomerular density was increased in SmoM2;Hoxb7-Cre mutant mice. The expression of Patched 1, the receptor of Shh and a downstream target gene of the Shh signaling pathway, was highly restricted and it was upregulated in the inner medullary collecting ducts of the kidney. The proliferative cells in the mesenchyme and collecting ducts were decreased in SmoM2;Hoxb7-Cre mutant mice. This study showed for the first time that sustained Smo inhibits postnatal kidney development by suppressing the proliferation of the mesenchyme and medullary collecting ducts in mice.
音猬因子（Shh）信号在肾脏发育过程中的调节、模式形成和增殖中起主要作用且至关重要。 smoothened（Smo）在转导Shh-胶质瘤相关癌基因Kruppel家族成员中起关键作用。然而，Smo持续激活在出生后肾脏发育中的作用所涉及的细胞和分子机制仍不清楚。利用一种条件性敲入小鼠模型，该模型在同源盒B7介导的重组（Hoxb7-Cre）后表达组成型激活形式的Smo（SmoM2），确定了Shh信号在出生后肾脏发育中的作用。SmoM2;Hoxb7-Cre突变小鼠表现出生长迟缓，体重减轻。肾脏集合管中Smo的组成型激活导致肾发育不全、肾积水和输尿管积水。SmoM2;Hoxb7-Cre突变小鼠的实质面积和肾小球数量减少，但肾小球密度增加。Shh的受体及Shh信号通路的下游靶基因Patched 1的表达受到高度限制，且在肾脏内髓集合管中上调。SmoM2;Hoxb7-Cre突变小鼠间充质和集合管中的增殖细胞减少。这项研究首次表明，持续的Smo通过抑制小鼠间充质和髓质集合管的增殖来抑制出生后肾脏发育。
