Direct visualization of Smad1/5/8-mediated transcriptional activity identifies podocytes and collecting ducts as major targets of BMP signalling in healthy and diseased kidneys
Direct visualization of Smad1/5/8-mediated transcriptional activity identifies podocytes and collecting ducts as major targets of BMP signalling in healthy and diseased kidneys
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DOI：
10.1002/path.2844
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发表时间：
2011-05-01
影响因子：
7.3
通讯作者：
Goldschmeding, Roel
中科院分区：
文献类型：
--
作者：
Leeuwis, Jan Willem;Nguyen, Tri Q.;Goldschmeding, Roel
骨形态发生蛋白 7 (BMP7) 是肾脏对损伤反应的关键决定因素，在各种实验模型中表现出强大的保护和再生潜力。在体外，已在许多肾细胞类型中观察到 BMP7 和其他 BMP 刺激的有益效果。尽管如此，人们对于健康和疾病中天然肾脏中哪些细胞实际上对 BMP 做出反应仍知之甚少。在这里，我们报告使用在 pSmad1/5/8 特异性 BMP 响应元件 (BRE) 控制下表达绿色荧光蛋白 (GFP) 的 BRE:gfp 小鼠来直接可视化健康肾脏和两种不同肾脏疾病模型中典型 BMP 信号下游转录活性的时空分布。 BRE-GFP 信号与内源 BMP 靶基因的表达一致，但令人惊讶的是，它比 pSmad1/5/8（典型 BMP 信号转导的经典组成部分）的广泛分布所预期的要严格得多。 BRE-GFP主要存在于足细胞和集合管细胞中，缺血再灌注损伤以及单侧输尿管梗阻后肾小球和髓质BRE-GFP均减少，同时BMP7、pSmad1/5/8和BMP靶基因表达减少。然而值得注意的是，受损的近端肾小管中 BRE-GFP 的增加与 BMP 受体 ALK2 和 ALK3 的上调有关。因此，天然 BMP 转录活性比之前仅基于 pSmad1/5/8 检测所建议的受到更多限制，并且其对损伤的反应根据细胞类型和肾单位片段而变化。版权所有 (C) 2011 大不列颠及爱尔兰病理学会。由约翰·威利父子有限公司出版
Bone morphogenetic protein 7 (BMP7) is a key determinant of renal response to injury, exhibiting strong protective as well as regenerative potential in a variety of experimental models. In vitro, beneficial effects of stimulation with BMP7 and other BMPs have been observed in many renal cell types. Still, it remains poorly understood which cells in the native kidney actually respond to BMPs in health and disease. Here, we report the use of BRE:gfp mice expressing green fluorescent protein (GFP) under the control of a pSmad1/5/8-specific BMP-responsive element (BRE) to directly visualize the spatiotemporal distribution of transcriptional activity downstream of canonical BMP signalling in healthy kidneys and in two distinct models of kidney disease. BRE-GFP signal coincided with expression of endogenous BMP target genes but, surprisingly, it was much more restricted than expected from the widespread distribution of pSmad1/5/8, a classical component of canonical BMP signal tranduction. BRE-GFP was mainly present in podocytes and collecting duct cells, and both glomerular and medullary BRE-GFP decreased following ischaemia-reperfusion injury as well as following unilateral ureteric obstruction, together with decreased BMP7, pSmad1/5/8 and BMP target gene expression. Remarkably, however, BRE-GFP was increased in injured proximal tubules in association with up-regulation of BMP receptors ALK2 and ALK3. Thus, native BMP transcriptional activity is much more restricted than previously suggested based on pSmad1/5/8 detection alone, and its response to injury varies according to cell type and nephron segment. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.