Chung Hyunjae, Rahmani Waleed, Sinha Sarthak, Imanzadeh Aysa, Pun Alexander, Arora Rohit, Jaffer Arzina, Biernaskie Jeff, Chun Justin
Department of Medicine, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Stem Cells. 2025 May 15;43(5). doi: 10.1093/stmcls/sxaf012.
The renin-angiotensin system (RAS) is essential for normal kidney development. Dysregulation of the RAS during embryogenesis can result in kidney abnormalities. To explore how angiotensin type 1 receptor (AT1R) signaling modulates nephron progenitor (NP) fate specification, we used induced pluripotent stem cell (iPSC) derived human kidney organoids treated with angiotensin II (Ang II) or the AT1R blocker losartan during differentiation. Ang II promoted NP proliferation and differentiation preferentially toward a podocyte fate, depleted the podocyte precursor population, and accelerated glomerular maturation. By contrast, losartan expanded the podocyte precursor population, delayed podocyte differentiation, and regressed the transcriptional signature to a more immature fetal state. Overall, using various in silico approaches with validation by RNAscope, we identified a role for AT1R signaling in regulating NP fate during nephrogenesis in kidney organoids. Our work supports the use of RAS modulators to improve organoid maturation and suggests that RAS may be a determinant of nephron endowment in vivo.
肾素-血管紧张素系统（RAS）对正常肾脏发育至关重要。胚胎发生过程中RAS的失调可导致肾脏异常。为了探究血管紧张素1型受体（AT1R）信号如何调节肾单位祖细胞（NP）的命运决定，我们在分化过程中使用了用血管紧张素II（Ang II）或AT1R阻滞剂氯沙坦处理的诱导多能干细胞（iPSC）衍生的人肾脏类器官。Ang II促进NP增殖并优先向足细胞命运分化，耗尽足细胞前体细胞群，并加速肾小球成熟。相比之下，氯沙坦扩大了足细胞前体细胞群，延迟了足细胞分化，并使转录特征退回到更不成熟的胎儿状态。总体而言，我们使用各种计算机方法并通过RNAscope进行验证，确定了AT1R信号在调节肾脏类器官肾发生过程中NP命运方面的作用。我们的工作支持使用RAS调节剂来改善类器官成熟，并表明RAS可能是体内肾单位禀赋的决定因素。
