Nephron-associated Support Cell Transcriptional Plasticity Expands in Hypertension

Abstract Hypertension (HTN) affects over one billion people worldwide and can lead to debilitating cardiovascular and renal conditions if left untreated. Cell death in the kidneys and the inflammation that follows are among the primary effects of chronically elevated blood pressure. There are several cell types throughout the body with immunomodulatory, anti-inflammatory, and pro-regenerative properties that support tissue homeostasis and recent studies have highlighted their therapeutic potential in HTN and kidney-related conditions. In our previous paper, we found a pool of multipotent nephron-associated support cells (SCs) in single-cell RNA sequencing samples of CD31+ and podoplanin+ cells taken from the kidneys of hypertensive mice generated through two mouse models of HTN. Despite remaining roughly constant in number between HTN and control groups, these SCs had 299 differentially expressed genes (p<0.01), 51 and 86 enriched pathways (p<0.01) in the M2 and M5 Molecular Signatures Database gene sets, respectively, and 180 HTN-specific regulons. We also compared lymphatic endothelial cells (LECs) and SCs from HTN and control groups and identified 3636 differentially expressed genes (p<0.01), 537 M2 and 415 M5 enriched pathways (p<0.01), and 218 LEC-specific and 227 SC-specific regulons in the HTN samples. SCs from mice with HTN were more resistant to inflammation-induced changes compared to LECs, and had downregulated stem cell suppressive genes and upregulated genes related to stem cell proliferation and regeneration. Graphical Abstract Created with BioRender.com Competing Interest Statement The authors have declared no competing interest.