Department of Urology, Harvard Medical School, Boston, MA 02115, USA.
School of Dentistry and Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R7, Canada.
Development. 2022 Jul 15;149(14). doi: 10.1242/dev.200773. Epub 2022 Jul 25.
The mammalian kidney is composed of thousands of nephrons that are formed through reiterative induction of a mesenchymal-to-epithelial transformation by a population of nephron progenitor cells. The number of nephrons in human kidneys ranges from several hundred thousand to nearly a million, and low nephron number has been implicated as a risk factor for kidney disease as an adult. Bmp7 is among a small number of growth factors required to support the proliferation and self-renewal of nephron progenitor cells, in a process that will largely determine the final nephron number. Once induced, each nephron begins as a simple tubule that undergoes extensive proliferation and segmental differentiation. Bmp7 is expressed both by nephron progenitor cells and the ureteric bud derivative branches that induce new nephrons. Here, we show that, in mice, Bmp7 expressed by progenitor cells has a major role in determining nephron number; nephron number is reduced to one tenth its normal value in its absence. Postnatally, Bmp7 also drives proliferation of the proximal tubule cells, and these ultimately constitute the largest segment of the nephron. Bmp7 appears to act through Smad 1,5,9(8), p38 and JNK MAP kinase. In the absence of Bmp7, nephrons undergo a hypertrophic process that involves p38. Following a global inactivation of Bmp7, we also see evidence for Bmp7-driven growth of the nephron postnatally. Thus, we identify a role for Bmp7 in supporting the progenitor population and driving expansion of nephrons to produce a mature kidney.
哺乳动物的肾脏由数千个肾单位组成，这些肾单位是通过一群肾祖细胞的间质到上皮的反复诱导形成的。人类肾脏中的肾单位数量从几十万到近百万不等，肾单位数量少被认为是成年后患肾脏疾病的一个风险因素。Bmp7 是少数几种支持肾祖细胞增殖和自我更新所需的生长因子之一，这一过程在很大程度上决定了最终的肾单位数量。一旦被诱导，每个肾单位最初都是一个简单的小管，经历广泛的增殖和节段性分化。Bmp7 既由肾祖细胞表达，也由输尿管芽衍生物分支表达，后者诱导新的肾单位。在这里，我们表明，在小鼠中，祖细胞表达的 Bmp7 在决定肾单位数量方面起着主要作用；在没有 Bmp7 的情况下，肾单位数量减少到正常数量的十分之一。出生后，Bmp7 还驱动近端小管细胞的增殖，这些细胞最终构成了肾单位的最大部分。Bmp7 似乎通过 Smad 1、5、9(8)、p38 和 JNK MAP 激酶发挥作用。在没有 Bmp7 的情况下，肾单位会发生涉及 p38 的肥大过程。在 Bmp7 被全局失活后，我们也看到了 Bmp7 驱动出生后肾单位生长的证据。因此，我们确定了 Bmp7 在支持祖细胞群体和驱动肾单位扩张以产生成熟肾脏方面的作用。
