Membranous Nephropathy Target Antigens Display Podocyte-Specific and Non-Specific Expression in Healthy Kidneys.

Area of Science:

• Nephrology
• Immunology
• Genomics

Background:

• Autoimmunity against podocyte antigens is a primary cause of membranous nephropathy (MN).
• Numerous MN target antigens (MNTAgs) have been identified, but their expression in podocytes remains largely uncharacterized.
• Understanding podocyte expression of MNTAgs is crucial for diagnosing and treating MN.

Purpose of the Study:

• To investigate the expression patterns of known MNTAgs in adult, fetal, and mouse podocytes.
• To identify potential MNTAgs relevant to different age groups and species.
• To correlate MNTAg expression with podocyte injury and disease states.

Main Methods:

• Utilized CZ CELLxGene single-cell RNA sequencing datasets from adult, fetal, and mouse kidneys.
• Analyzed the expression of a comprehensive list of MNTAgs, including PLA2R1, THSD7A, and others.
• Examined chromatin accessibility data to infer transcriptional regulation of MNTAg expression.

Main Results:

• Most MNTAgs are expressed in adult podocytes, with PLA2R1 showing significantly higher enrichment and acting as a major podocyte marker.
• PLA2R1 is upregulated in podocytes across various kidney diseases associated with proteinuria.
• SEMA3B is highly expressed in fetal podocytes, suggesting its role as a childhood MNTAg, while Thsd7a is prominent in mouse podocytes.

Conclusions:

• The majority of MNTAgs are expressed in podocytes during both adult life and renal development.
• PLA2R1 is a critical podocyte marker in adults, with its elevated expression linked to kidney diseases and proteinuria.
• Specific MNTAgs like SEMA3B and Thsd7a show distinct expression patterns in fetal and mouse kidneys, respectively, highlighting species- and developmental-specific roles.