Abstract: TH-PO0392
The Nonsteroidogenic Panmelanocortin Receptor Agonist (Nle4, D-Phe7)-α-Melanocyte-Stimulating Hormone Ameliorates THSD7A-Associated Membranous Nephropathy in an Active Immunization Mouse Model
Session Information
- Glomerular Diseases: Genetics to Therapeutics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Zhang, Mingzhuo, Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, United States
- Chen, Mengxuan, Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, United States
- Gong, Rujun, Division of Nephrology, Department of Medicine, University of Toledo College of Medicine, Toledo, Ohio, United States
Background
Melanocortin-based therapies have demonstrated protective effects in experimental membranous nephropathy (MN). However, existing evidence is derived exclusively from passive immunization models, which do not fully recapitulate the autoimmune mechanisms underlying human MN, thereby limiting translational relevance. This study aimed to establish a clinically relevant active immunization mouse model of THSD7A-associated MN using a commercially available THSD7A antigen and to evaluate the therapeutic effects of melanocortin in this setting.
Methods
MN was induced in mice by repeated immunization with a commercial recombinant mouse THSD7A emulsified in Freund’s adjuvant. One week after the final immunization, when proteinuria and glomerular injury were established, mice were treated with the potent non-steroidogenic pan-melanocortin receptor agonist [Nle4, D-Phe7]-α-melanocyte-stimulating hormone (NDP-MSH) or vehicle for three weeks. Urinary, serological, and renal histopathological parameters were subsequently assessed.
Results
This active immunization model successfully recapitulated key features of human MN, including insidious onset, progressive proteinuria, and characteristic histopathology such as subepithelial immune deposition, complement activation along glomerular capillary loops, glomerular basement membrane thickening, and podocyte injury with foot process effacement and loss of homeostatic markers. Therapeutic intervention with the pan–melanocortin receptor agonist NDP-MSH significantly reduced proteinuria and attenuated glomerular and podocyte injury, accompanied by decreased circulating anti-THSD7A autoantibody levels, reduced glomerular immune deposition, and diminished complement activation. Mechanistically, ex vivo studies of primed B cells showed that NDP-MSH inhibited plasma cell differentiation and autoantibody production, associated with upregulation of microphthalmia-associated transcription factor (MITF) and downregulation of interferon regulatory factor 4 (IRF4), consistent with activation of the MITF/IRF4 axis.
Conclusion
Collectively, these findings extend the therapeutic potential of melanocortin to a clinically relevant model of MN and provide mechanistic insight into its immunomodulatory actions, supporting further investigation of targeted melanocortin-based therapies.
Funding
- NIDDK Support