Single cell sequencing of renal endothelial cell heterogeneity and metabolic transcriptome adaptation to dehydration.. Single cell sequencing of renal endothelial cell heterogeneity and metabolic transcriptome adaptation to dehydration.

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.

来源于肾脏肾小球、皮质与髓质区域的肾内皮细胞（Renal endothelial cells, RECs）所处的微环境存在显著差异。当机体脱水时，髓质肾内皮细胞（medullary RECs, 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仍尚未完成全面编目，且髓质肾内皮细胞如何应对脱水应激的机制尚不明确。
本研究通过对超过40000个肾内皮细胞开展单细胞RNA测序，鉴定出24种肾内皮细胞表型（其中8种为全新表型），揭示了肾小球、皮质及髓质内部以及各区域之间肾内皮细胞均存在广泛的异质性。
脱水应激条件下，髓质肾内皮细胞主要上调了参与缺氧应答、糖酵解以及令人意外的氧化磷酸化（oxidative phosphorylation, OXPHOS）相关基因的表达。
体外实验中，髓质肾内皮细胞在高渗刺激下会提升氧消耗速率，这一现象推测是为了维持钠钾ATP酶（Na+/K+ ATPase pump）介导的盐分排泄所需的ATP生成，并通过氧化磷酸化过程产生代谢水以抵消髓质肾内皮细胞的高渗状态，从而揭示了氧化磷酸化此前未被充分认知的生理作用。
综上，肾内皮细胞具备广泛的异质性与可塑性，可通过调控代谢转录组以适应并克服脱水应激。