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Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker

Author(s): Menon, Rajasree; Otto, Edgar A; Hoover, Paul; Eddy, Sean; Mariani, Laura; et al

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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.
Publication Date: 27-Feb-2020
Citation: Menon, Rajasree, 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, and Nephrotic Syndrome Study Network. "Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker." JCI insight 5, no. 6 (2020): e133267. doi:10.1172/jci.insight.133267
DOI: 10.1172/jci.insight.133267
EISSN: 2379-3708
Pages: e133267
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: JCI insight
Version: Author's manuscript



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