TY - JOUR
T1 - Molecular determinants of nephron vascular specialization in the kidney
AU - Barry, David M.
AU - McMillan, Elizabeth A.
AU - Kunar, Balvir
AU - Lis, Raphael
AU - Zhang, Tuo
AU - Lu, Tyler
AU - Daniel, Edward
AU - Yokoyama, Masataka
AU - Gomez-Salinero, Jesus M.
AU - Sureshbabu, Angara
AU - Cleaver, Ondine
AU - Di Lorenzo, Annarita
AU - Choi, Mary E.
AU - Xiang, Jenny
AU - Redmond, David
AU - Rabbany, Sina Y.
AU - Muthukumar, Thangamani
AU - Rafii, Shahin
N1 - Funding Information:
We are grateful to Dr. Anne M Moon for supplying the Tbx3tm3.1Moon mouse strain. T.M. is supported by the R03 National Institute of Digestive and Kidney Diseases (NIDDK) R03 DK105270 grant. M.E.C. is supported by National Institute of Health (NIH) R01 HL133801, R01 HL060234, R01 HL055330, and R01 HL132198. A.D.L. is supported by National Institute of Heart, Lung and Blood (NHLBI) R01 126913. S.R. is supported by Ansary Stem Cell Institute, Division of Regenerative Medicine at Weill Cornell Medicine (WCM), and National Institute of Health (NIH) Director’s Transformative award R01 HL128158 and National Heart, Lung, and Blood Institute (NHLBI) HL139056, National Institute of Allergy and Immunology (NIAID) U01 AI17001 and Daedalus fund for innovation Weill Cornell Medicine and New York State Stem Cell Science (NYSTEM) Consortium Award and Avalon GloboCare Corp training grant and Lisa Dean Moseley Foundation. This research was supported in part by National Cancer Institute (NCI) Grant NIH T32 CA203702.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-019-12872-5
DO - 10.1038/s41467-019-12872-5
M3 - Article
C2 - 31836710
AN - SCOPUS:85076306473
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5705
ER -