THSD7A-associated membranous nephropathy involves both complement-mediated and autonomous podocyte injury.

Area of Science:

• Nephrology
• Immunology
• Pathology

Background:

• Membranous nephropathy (MN) is a primary cause of nephrotic syndrome in adults.
• Thrombospondin type 1 domain containing 7A (THSD7A)-associated MN is a distinct subtype, with THSD7A expression in preclinical species enabling disease modeling.
• Previous THSD7A-MN mouse models relied on non-commercially available antibodies, limiting their accessibility.

Purpose of the Study:

• To develop and characterize a novel, accessible mouse model of THSD7A-associated MN using a commercially available antibody.
• To investigate the roles of complement-dependent and -independent pathways in THSD7A-MN pathogenesis.
• To evaluate the therapeutic potential of adrenocorticotropic hormone in this new model.

Main Methods:

• Induction of THSD7A-associated MN in mice using a commercially available anti-THSD7A antibody.
• Assessment of proteinuria and glomerular pathology.
• Complement depletion using cobra venom factor.
• In vitro studies on primary podocytes exposed to the antibody.
• Treatment with repository corticotropin injection (adrenocorticotropic hormone).

Main Results:

• The model exhibited heavy proteinuria and human MN-like pathology, with no sex differences.
• Complement depletion only partially reduced proteinuria and injury, indicating complement-independent mechanisms.
• In vitro, the antibody induced podocytopathy (cytoskeletal disruption, hypermobility, oxidative stress, apoptosis) independent of complement.
• Adrenocorticotropic hormone therapy significantly ameliorated proteinuria and glomerular injury.

Conclusions:

• A new, reproducible mouse model for THSD7A-associated MN was established using a commercially available antibody.
• Both complement-dependent and -independent pathways contribute to podocyte injury in THSD7A-MN.
• This model is valuable for studying MN pathogenesis and for preclinical testing of novel therapeutics, including adrenocorticotropic hormone.