Urine Single-Cell RNA Sequencing in Focal Segmental Glomerulosclerosis Reveals Inflammatory Signatures

Khun Zaw Latt, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Jurgen Heymann, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Joseph H. Jessee, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Avi Z. Rosenberg, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Celine C. Berthier, Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan, USA.
Arnon Arazi, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, USA.
Sean Eddy, Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan, USA.
Teruhiko Yoshida, Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Yongmei Zhao, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick, Maryland, USA.
Vicky Chen, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick, Maryland, USA.
George W. Nelson, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick, Maryland, USA.
Margaret Cam, Advanced Biomedical and Computational Sciences, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., National Cancer Institute, Frederick, Maryland, USA.
Parimal Kumar, Center for Cancer Research Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
Monika Mehta, Center for Cancer Research Sequencing Facility, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.
Michael C. Kelly, Cancer Research Technology Program, Single-Cell Analysis Facility, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Matthias Kretzler, Division of Nephrology, Department of Internal Medicine, Michigan Medicine, Ann Arbor, Michigan, USA.

Document Type

Journal Article

Publication Date

2-1-2022

Journal

Kidney international reports

Volume

7

Issue

2

DOI

10.1016/j.ekir.2021.11.005

Keywords

FSGS; inflammation and fibrosis; profibrotic signatures; single cell RNA-seq; urine biomarkers

Abstract

Introduction: Individuals with focal segmental glomerular sclerosis (FSGS) typically undergo kidney biopsy only once, which limits the ability to characterize kidney cell gene expression over time. Methods: We used single-cell RNA sequencing (scRNA-seq) to explore disease-related molecular signatures in urine cells from subjects with FSGS. We collected 17 urine samples from 12 FSGS subjects and captured these as 23 urine cell samples. The inflammatory signatures from renal epithelial and immune cells were evaluated in bulk gene expression data sets of FSGS and minimal change disease (MCD) (The Nephrotic Syndrome Study Network [NEPTUNE] study) and an immune single-cell data set from lupus nephritis (Accelerating Medicines Partnership). Results: We identified immune cells, predominantly monocytes, and renal epithelial cells in the urine. Further analysis revealed 2 monocyte subtypes consistent with M1 and M2 monocytes. Shed podocytes in the urine had high expression of marker genes for epithelial-to-mesenchymal transition (EMT). We selected the 16 most highly expressed genes from urine immune cells and 10 most highly expressed EMT genes from urine podocytes as immune signatures and EMT signatures, respectively. Using kidney biopsy transcriptomic data from NEPTUNE, we found that urine cell immune signature and EMT signature genes were more highly expressed in FSGS biopsies compared with MCD biopsies. Conclusion: The identification of monocyte subsets and podocyte expression signatures in the urine samples of subjects with FSGS suggests that urine cell profiling might serve as a diagnostic and prognostic tool in nephrotic syndrome. Furthermore, this approach may aid in the development of novel biomarkers and identifying personalized therapies targeting particular molecular pathways in immune cells and podocytes.

Department

Pediatrics

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