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.