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Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker
Rajasree Menon, … , Kidney Precision Medicine Project (KPMP), Nephrotic Syndrome Study Network (NEPTUNE)
Rajasree Menon, … , Kidney Precision Medicine Project (KPMP), Nephrotic Syndrome Study Network (NEPTUNE)
Published February 27, 2020
Citation Information: JCI Insight. 2020;5(6):e133267. https://doi.org/10.1172/jci.insight.133267.
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Research Article Cell biology Nephrology

Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker

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Abstract

To define cellular mechanisms underlying kidney function and failure, the KPMP analyzes biopsy tissue in a multicenter research network to build cell-level process maps of the kidney. This study aimed to establish a single cell RNA sequencing strategy to use cell-level transcriptional profiles from kidney biopsies in KPMP to define molecular subtypes in glomerular diseases. Using multiple sources of adult human kidney reference tissue samples, 22,268 single cell profiles passed KPMP quality control parameters. Unbiased clustering resulted in 31 distinct cell clusters that were linked to kidney and immune cell types using specific cell markers. Focusing on endothelial cell phenotypes, in silico and in situ hybridization methods assigned 3 discrete endothelial cell clusters to distinct renal vascular beds. Transcripts defining glomerular endothelial cells (GEC) were evaluated in biopsies from patients with 10 different glomerular diseases in the NEPTUNE and European Renal cDNA Bank (ERCB) cohort studies. Highest GEC scores were observed in patients with focal segmental glomerulosclerosis (FSGS). Molecular endothelial signatures suggested 2 distinct FSGS patient subgroups with α-2 macroglobulin (A2M) as a key downstream mediator of the endothelial cell phenotype. Finally, glomerular A2M transcript levels associated with lower proteinuria remission rates, linking endothelial function with long-term outcome in FSGS.

Authors

Rajasree Menon, Edgar A. Otto, Paul Hoover, Sean Eddy, Laura Mariani, Bradley Godfrey, Celine C. Berthier, Felix Eichinger, Lalita Subramanian, Jennifer Harder, Wenjun Ju, Viji Nair, Maria Larkina, Abhijit S. Naik, Jinghui Luo, Sanjay Jain, Rachel Sealfon, Olga Troyanskaya, Nir Hacohen, Jeffrey B. Hodgin, Matthias Kretzler, Kidney Precision Medicine Project (KPMP), Nephrotic Syndrome Study Network (NEPTUNE)

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Figure 9

Integrated analysis of scRNAseq and bulk mRNAseq data.

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Integrated analysis of scRNAseq and bulk mRNAseq data.
(A) Two distinct ...
(A) Two distinct groups from the hierarchical clustering of the 78 glomerular endothelial cell defining mRNA transcripts in isolated glomeruli of FSGS biopsy samples from the NEPTUNE cohort. (B) Kidney-specific functional module gene interaction network (https://hb.flatironinstitute.org). The figure shows the 3 significant functional modules and their interactions. (C) Protein interaction network generated using STRING for the top 100 genes that were substantially overexpressed in group 2 versus group 1. (D) Top upstream regulators predicted by IPA. The bar plots show the activation scores predicted by IPA for the top 5 upstream regulators (P < 0.05 by Fisher’s exact test). (E) The regulatory interaction of the top 2 regulators, VEGF growth factor, and STAT1 show A2M as a downstream target. FSGS, focal segmental glomerulosclerosis.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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