Abstract: TH-PO0666
Melanocortin Therapy Mitigates Glomerular Complement Activation and Podocyte Injury in Membranous Nephropathy via MC5R Signaling
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Liu, Jing, The University of Toledo Medical Center, Toledo, Ohio, United States
- Zhang, Mingzhuo, The University of Toledo Medical Center, Toledo, Ohio, United States
- Alkhatib, Kamel, ANI Pharmaceuticals Inc, Baudette, Minnesota, United States
- Dworkin, Lance D., The University of Toledo Medical Center, Toledo, Ohio, United States
- Gong, Rujun, The University of Toledo Medical Center, Toledo, Ohio, United States
Background
Melanocortins, particularly ACTH, have shown potential in the treatment of membranous nephropathy (MN). The underlying mechanisms remain unclear. This study examined the role of melanocortin 5 receptor (MC5R), which has been identified in glomeruli.
Methods
A heterologous model of THSD7A-associated MN was developed in wild-type (WT) and MC5R knockout (KO) mice, and treated with melanocortins, including the repository corticotropin injection (Purified Cortrophin® Gel, ANI Pharmaceuticals, Inc), the non-steroidogenic pan-melanocortin receptor agonist NDP-MSH, and the selective MC5R agonist PG-901. Additional KO mice underwent hydrodynamic gene delivery beforehand for podocyte-specific reconstitution of MC5R.
Results
Melanocortin therapy ameliorated MN in mice, as evidenced by reduced proteinuria and improved podocytopathy and renal pathology characteristic of human MN. In contrast, MC5R KO exacerbated MN, while abolishing the beneficial effects of melanocortins. MC5R expression was evident in podocytes of WT mice, and podocyte MC5R appears to protect against MN, as demonstrated by its necessity for melanocortin protection in cultured podocytes, and restoration of melanocortin therapeutic efficacy in KO mice after podocyte-specific reconstitution of MC5R. Mechanistically, glomerular fixation of C5b-9 and C3 was reduced with melanocortin therapy in diseased WT mice but increased by MC5R KO, despite similar glomerular deposition of the nephritogenic antibody and activation of C4, suggesting that MC5R signaling exerts an anti-complement effect primarily through mitigating C3 amplification. Comprehensive complement cascade analysis further revealed that this anti-complement effect of MC5R signaling likely stems from an inhibition of podocyte expression of complement factor B (CFB) and CFD—critical regulators of the complement amplification loop—both of which are overexpressed in glomeruli of MN patients, according to Nephroseq database analyses. In consistency, unbiased transcriptomic analysis of the publicly available renal transcriptome data from ACTH- and vehicle-treated mice indicated a marked suppression of renal expression of CFB and CFD following ACTH treatment.
Conclusion
MC5R signaling intercepts the complement amplification loop in podocytes, thereby mitigating glomerular injury in experimental MN.
Funding
- Commercial Support – ANI Pharmaceuticals, Inc.