Kidney Week

Abstract: TH-PO0419

Melanocortin Therapy Attenuates Autoreactive Humoral Immune Response and Ameliorates Glomerular Injury in Active Heymann Nephritis

Session Information

• Glomerular Diseases: Autoimmune Diseases
  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, University of Toledo College of Medicine, Toledo, Ohio, United States

Mingzhuo Zhang, MD

• Chen, Mengxuan, Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio, United States

Mengxuan Chen, MD

• Trewet, Coralynn Becker, ANI Pharmaceuticals Inc, Baudette, Minnesota, United States

Coralynn Becker Trewet, PharmD

• Alkhatib, Kamel, ANI Pharmaceuticals Inc, Baudette, Minnesota, United States

Kamel Alkhatib, PhD

• Gong, Rujun, Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio, United States

Rujun Gong, MD, PhD, FASN

Background

Melanocortins, particularly adrenocorticotropic hormone (ACTH), have demonstrated therapeutic benefit in primary membranous nephropathy (MN). Notably, ACTH-induced clinical improvement in MN, including in steroid-resistant cases, is frequently preceded by immunological remission, implying a potential steroidogenesis-independent immunomodulatory effect of melanocortin signaling on humoral immunity. To test this premise, we evaluated the effect of melanocortin therapy on active Heymann nephritis (AHN), an autoimmune model of human MN.

Methods

AHN was induced in Lewis rats by repeated immunization with Fx1A emulsified in Freund’s adjuvant. Two weeks after the final immunization, when proteinuria and glomerular injury were evident, animals were treated with melanocortins, including Repository Corticotropin Injection (RCI; Purified Cortrophin® Gel, ANI Pharmaceuticals, Inc.) containing porcine derived ACTH_1–39, the non-steroidogenic pan–melanocortin receptor (MCR) agonist NDP-MSH, or the selective MC1R agonist MS05. Gelatin gel or phosphate-buffered saline served as vehicle control treatment.

Results

AHN rats developed severe proteinuria and glomerular injury, marked by loss of the podocyte homeostatic protein podocin and de novo podocyte expression of desmin. These changes were accompanied by diffuse, pseudo-linear deposition of granular nephritogenic IgG and complement C5b-9 within the glomeruli. RCI treatment substantially reduced proteinuria, preserved podocyte integrity, and attenuated glomerular IgG and C5b-9 deposition. Similar renoprotective effects were observed with NDP-MSH, indicating steroid independent mechanisms of action. Selective MC1R agonism by MS05 likewise improved proteinuria and glomerular injury while reducing immune complex and complement deposition. Importantly, circulating autoreactive IgG against Fx1A was reduced by all melanocortin treatments. The efficacy of MS05 indicates that MC1R activation alone is sufficient to suppress autoreactive IgG production, supporting a central and minimally sufficient role for MC1R in modulating humoral autoimmunity.

Conclusion

Melanocortin therapy attenuates autoreactive humoral immune response and confers glomerular protection in AHN, at least in part via MC1R activation. Targeting melanocortin signaling pathways represents a promising immunomodulatory strategy for the treatment of MN.

Funding

• Commercial Support – ANI Pharmaceuticals, Inc.