Identification of a Podocyte-Derived Cytokine as a Potential Mediator of Injury in FSGS via Single-Cell RNA Sequencing of Human Kidney Tissue
- Glomerular Diseases: Podocyte Biology - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
- Dalal, Vidhi, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
- Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Hayashida, Tomoko, Horizon Pharma Inc United States Operations, Lake Forest, Illinois, United States
- Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Focal segmental glomerulosclerosis (FSGS) is a major cause of end stage kidney disease (ESKD) worldwide, and patients with primary and genetic forms of FSGS are frequently resistant to existing treatments. As such, there is a strong need for the development of new treatments for FSGS. There is evidence that cytokines may play a role in the pathogenesis of FSGS. Most of this evidence is based on immune cell-derived cytokines, and little is known about podocyte-derived cytokines in FSGS. The podocyte has been shown to produce cytokines and even act as an antigen presenting cell in other forms of kidney disease, but its role as an immune cell in FSGS has not yet been explored. That is the aim of our study.
Single cell RNA sequencing performed on kidney tissue from a patient with a genetic form of FSGS revealed increased expression of two different interleukins in the patient’s podocytes versus podocytes from healthy kidneys. Because one of these interleukins, hereby referred to as interleukin (IL)-X, has also been shown to promote injury in other forms of kidney disease, we evaluated the expression of IL-X and NPHS2 in kidney tissue from patients with primary and genetic forms of FSGS via RNA scope.
Baseline glomerular expression of IL-X was low to virtually undetectable in control kidneys. When IL-X was detected in control kidneys, it was seen in intercalated cells and immune cells that were negative for NPHS2 with only faint staining seen in the rare NPHS2+ podocyte. In kidneys with FSGS, both primary and genetic forms, IL-X was seen in NPHS2+ podocytes more frequently, and the IL-X signal in podocytes was consistently stronger in diseased kidneys than in control kidneys. Notably, single cell RNA sequencing data from the patient with genetic FSGS indicated that the receptor for IL-X was expressed primarily on lymphocytes.
Our findings indicate that IL-X expression is increased in podocytes in both primary and genetic forms of FSGS. Given that the receptor for IL-X is expressed primarily on lymphocytes, we hypothesize that podocyte-derived IL-X recruits inflammatory cells to the glomerulus to propagate injury. We will use in vivo and in vitro models to define the role of IL-X in the pathogenesis of FSGS and to determine its utility as a therapeutic target in FSGS.
- NIDDK Support