Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Kidney Regenerative Medicine Laboratory, The Rogosin Institute, New York, NY 10065, USA.
Development. 2022 Jan 1;149(1). doi: 10.1242/dev.199984. Epub 2022 Jan 4.
Expansion of interstitial cells in the adult kidney is a hallmark of chronic disease, whereas their proliferation during fetal development is necessary for organ formation. An intriguing difference between adult and neonatal kidneys is that the neonatal kidney has the capacity to control interstitial cell proliferation when the target number has been reached. In this study, we define the consequences of inactivating the TGFβ/Smad response in the mouse interstitial cell lineage. We find that pathway inactivation through loss of Smad4 leads to overproliferation of interstitial cells regionally in the kidney medulla. Analysis of markers for BMP and TGFβ pathway activation reveals that loss of Smad4 primarily reduces TGFβ signaling in the interstitium. Whereas TGFβ signaling is reduced in these cells, marker analysis shows that Wnt/β-catenin signaling is increased. Our analysis supports a model in which Wnt/β-catenin-mediated proliferation is attenuated by TGFβ/Smad to ensure that proliferation ceases when the target number of interstitial cells has been reached in the neonatal medulla.
成年肾脏间质细胞的扩张是慢性疾病的一个标志，而在胎儿发育过程中，它们的增殖对于器官形成是必要的。成年肾脏和新生儿肾脏之间一个有趣的区别是，当达到目标数量时，新生儿肾脏有能力控制间质细胞的增殖。在这项研究中，我们定义了在小鼠间质细胞谱系中失活 TGFβ/Smad 反应的后果。我们发现，通过缺失 Smad4 使通路失活会导致肾脏髓质局部间质细胞过度增殖。对 BMP 和 TGFβ 通路激活标志物的分析表明，Smad4 的缺失主要减少了间质中的 TGFβ 信号。虽然这些细胞中的 TGFβ 信号减少，但标志物分析表明 Wnt/β-连环蛋白信号增加。我们的分析支持这样一种模型，即 Wnt/β-连环蛋白介导的增殖被 TGFβ/Smad 减弱，以确保在新生儿髓质中达到间质细胞的目标数量时增殖停止。
