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Abstract
Although kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task. The molecular pathways that specify and sustain functional, phenotypic and structural heterogeneity of the kidney vasculature are unknown. Here, we employ high-throughput bulk and single-cell RNA sequencing of the non-lymphatic endothelial cells (ECs) of the kidney to identify the molecular pathways that dictate vascular zonation from embryos to adulthood. We show that the kidney manifests vascular-specific signatures expressing defined transcription factors, ion channels, solute transporters, and angiocrine factors choreographing kidney functions. Notably, the ontology of the glomerulus coincides with induction of unique transcription factors, including Tbx3, Gata5, Prdm1, and Pbx1. Deletion of Tbx3 in ECs results in glomerular hypoplasia, microaneurysms and regressed fenestrations leading to fibrosis in subsets of glomeruli. Deciphering the molecular determinants of kidney vascular signatures lays the foundation for rebuilding nephrons and uncovering the pathogenesis of kidney disorders.
Highlights
Kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task
When we compared glomerular genes that were upregulated in Tbx3ΔEC mouse kidney endothelial cells (ECs) and Tbx3regulated genes in human umbilical vein endothelial cells (HUVECs), we find a high concordance with glomerular genes identified through scRNA-seq
We find that genes modified in response to overexpression of each transcription factor very highly overlap with genes expressed in the human glomerulus (Fig. 4t)
Summary
Kidney parenchymal tissue can be generated in vitro, reconstructing the complex vasculature of the kidney remains a daunting task. The vasa recta slow the rate of blood flow to maintain an osmotic gradient required for water reabsorption To execute these complex functions, the kidney vasculature has acquired adaptive structural and functional specialization often referred to as vascular zonation[9]. We use bulk and single-cell RNA sequencing (RNA-seq) of the kidney vasculature over a broad range of developmental and adult stages of organogenesis to allow the discovery of distinct transcriptomic signatures associated with different kidney vascular beds. This approach unravels the progression of molecular pathways that specify kidney vascular heterogeneity. Our data uncovers how the transcriptional ontology of the vasculature regulates nutrients and waste in the kidney to sustain chemical and vasomodulatory homeostasis
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