Abstract：
Renin is the key enzyme of the systemic renin-angiotensin-aldosterone system, which plays an essential role in regulating blood pressure and maintaining electrolyte and extracellular volume homeostasis. Renin is mainly produced and secreted by specialized juxtaglomerular (JG) cells in the kidney. In the present study, we report for the first time that the conserved transmembrane receptor neuropilin-1 (NRP1) participates in the development of JG cells and plays a key role in renin production. We used the myelin protein zero-Cre (P0-Cre) to abrogate Nrp1 constitutively in P0-Cre lineage-labelled cells of the kidney. We found that the P0-Cre precursor cells differentiate into renin-producing JG cells. We employed a lineage-tracing strategy combined with RNAscope quantification and metabolic studies to reveal a cell-autonomous role for NRP1 in JG cell function. Nrp1-deficient animals displayed abnormal levels of tissue renin expression and failed to adapt properly to a homeostatic challenge to sodium balance. These findings provide new insights into cell fate decisions and cellular plasticity operating in P0-Cre-expressing precursors and identify NRP1 as a novel key regulator of JG cell maturation. KEY POINTS: Renin is a centrepiece of the renin-angiotensin-aldosterone system and is produced by specialized juxtaglomerular cells (JG) of the kidney. Neuropilin-1 (NRP1) is a conserved membrane-bound receptor that regulates vascular and neuronal development, cancer aggressiveness and fibrosis progression. We used conditional mutagenesis and lineage tracing to show that NRP1 is expressed in JG cells where it regulates their function. Cell-specific Nrp1 knockout mice present with renin paucity in JG cells and struggle to adapt to a homeostatic challenge to sodium balance. The results support the versatility of renin-producing cells in the kidney and may open new avenues for therapeutic approaches.
摘要：
肾素是系统性肾素-血管紧张素-醛固酮系统的关键酶,在调节血压和维持电解质和细胞外体积稳态方面起着至关重要的作用。肾素主要由肾脏中的特化近球(JG)细胞产生和分泌。在本研究中,我们首次报道了保守的跨膜受体神经纤毛蛋白1(NRP1)参与JG细胞的发育,并在肾素的产生中起关键作用。我们使用髓磷脂蛋白零Cre（P0-Cre）在P0-Cre谱系标记的肾脏细胞中组成性地废除Nrp1。我们发现P0-Cre前体细胞分化成产生肾素的JG细胞。我们采用谱系追踪策略与RNAscope定量和代谢研究相结合，以揭示NRP1在JG细胞功能中的细胞自主作用。缺乏Nrp1的动物表现出异常的组织肾素表达水平，并且未能适当适应钠平衡的稳态挑战。这些发现为在P0-Cre表达前体中操作的细胞命运决定和细胞可塑性提供了新的见解，并将NRP1鉴定为JG细胞成熟的新型关键调节因子。要点：肾素是肾素-血管紧张素-醛固酮系统的核心，由肾脏的特化近球细胞（JG）产生。Neuropilin-1（NRP1）是一种保守的膜结合受体，可调节血管和神经元的发育，癌症侵袭性和纤维化进展。我们使用条件诱变和谱系追踪显示NRP1在JG细胞中表达，在那里它调节其功能。细胞特异性Nrp1敲除小鼠在JG细胞中存在肾素缺乏，并努力适应钠平衡的稳态挑战。结果支持肾脏中肾素产生细胞的多功能性，并可能为治疗方法开辟新的途径。
