Single-Cell RNA Sequencing Reveals Renal Endothelium Heterogeneity and Metabolic Adaptation to Water Deprivation

Renal endothelial cells (RECs) from glomerular cortical and medullary kidney compartments are exposed to different microenvironmental conditions. Upon dehydration medullary RECs (mRECs) are exposed to extreme hyperosmolarity. However the heterogeneous phenotypes of RECs remain in-completely inventoried and how mRECs respond to dehydration is unknown. By single cell RNA-sequencing of >40000 RECs we identified 24 (including 8 novel) REC phenotypes highlighting extensive heterogeneity of RECs between and within the cortex glomeruli and medulla. In response to dehydration mRECs upregulated primarily the expression of genes involved in the hypoxia response glycolysis and surprisingly oxidative phosphorylation (OXPHOS). In vitro mRECs increased oxygen consumption in response to hyperosmolarity presumably to sustain ATP production for Na+/K+ ATPase pump-mediated salt excretion and to generate metabolic water during OXPHOS in order to counteract mREC hyperosmolarity unveiling a previously underappreciated role of OXPHOS. Overall RECs exhibit extensive heterogeneity and plasticity to adapt their metabolic transcriptome to overcome dehydration.肾内皮细胞（renal endothelial cells, RECs）可分为源自肾脏肾小球皮质区与髓质区的两类，二者所处的微环境条件存在显著差异。当机体发生脱水时，髓质来源的肾内皮细胞（medullary renal endothelial cells, mRECs）会暴露于极端高渗环境中。然而，目前肾内皮细胞的异质性表型尚未被完整编目，且髓质肾内皮细胞如何响应脱水刺激的分子机制仍未阐明。本研究通过对超过40000个肾内皮细胞进行单细胞RNA测序，鉴定出24种肾内皮细胞表型（其中8种为全新发现的表型），揭示了肾内皮细胞在皮质、肾小球与髓质区域之间，以及各区域内部的广泛异质性。在脱水刺激下，髓质肾内皮细胞主要上调了参与缺氧应答、糖酵解的基因表达，而令人意外的是，还上调了与氧化磷酸化（oxidative phosphorylation, OXPHOS）相关的基因。体外实验结果显示，髓质肾内皮细胞在高渗刺激下会提升耗氧量，推测其目的在于维持ATP生成，以支撑钠钾ATP酶泵介导的盐分排泄过程，并通过氧化磷酸化过程产生代谢水，从而抵消自身所处的高渗环境；这一发现揭示了氧化磷酸化此前未被充分认知的生理功能。综上，肾内皮细胞具有广泛的异质性与可塑性，能够通过调控代谢相关转录组以适应并克服脱水应激。