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Abstract: TH-OR41

Hematopoietic-Specific Melanocortin 1 Receptor Signaling Protects Against Crescentic Glomerulonephritis and Mediates the Beneficial Effect of Melanocortin Therapy

Session Information

Category: Pathology and Lab Medicine

  • 1601 Pathology and Lab Medicine: Basic

Authors

  • Guan, Xuejing, Department of Medicine, Division of Nephrology, University of Toledo College of Medicine, Toledo, United States
  • Zhou, Rong, Department of Nephrology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
  • Dworkin, Lance D., Department of Medicine, Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio, United States
  • Gong, Rujun, Department of Medicine, Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio, United States
Background

Emerging evidence suggests that melanocortin 1 receptor (MC1R) signaling may contribute to
the beneficial action of melanocortins in glomerular diseases. However, whether hematopoietic MC1R signaling is implicated is unknown.

Methods

MC1R mutant (e/e) or wild-type (WT) mice were injured with rabbit nephrotoxic serum (NTS) and treated with melanocortins, including the Repository Corticotropin Injection (RCI, Acthar® Gel, Mallinckrodt ARD, LLC), NDP-MSH, and the MC1R selective agonist MS05. Some mice received adoptive transfer of syngeneic bone marrow-derived cells (BMDC) beforehand. Kidney function and injuries were evaluated.

Results

Upon NTS injury, e/e mice developed more severe crescentic glomerulonephritis than WT mice, featured by heavier proteinuria, higher serum creatinine levels and exacerbated renal lesions, including crescent formation, renal inflammatory infiltration and fibrosis as well as podocyte damage, marked by loss of expression of podocyte homeostatic markers in glomeruli. Melanocortin therapy substantially improved renal injury in WT mice and this protective effect was blunted in e/e mice. In contrast, adoptive transfer of BMDC derived from WT mice to e/e mice markedly ameliorated NTS nephritis and reinstated the therapeutic efficacy of melanocortins in e/e mice. Mechanistically, the beneficial action of WT BMDC in e/e mice was associated with diminished glomerular deposition of autologous anti-rabbit IgG and reduced fixation of C5b-9 along glomerular capillary loops, entailing a regulatory effect of BMDC-specific MC1R signaling on humoral immune response to NTS antigens. In addition, melanocortin therapy prominently tilted macrophage polarization towards the anti- inflammatory M2 phenotypes in NTS-injured kidneys in WT mice. MC1R signaling is likely involved in this modulation of macrophage behavior, because MC1R was evidently expressed in bone marrow-derived macrophage (BMM) prepared from WT mice but absent from e/e BMM. Furthermore, MS05 diminished M1 phenotypes and promoted M2 polarization in M1-primed WT BMM but not e/e BMM, thus denoting a pro-M2 skewing effect of MC1R signaling.

Conclusion

Hematopoietic MC1R signaling attenuates NTS nephritis via, at least in part, regulation of humoral immune response and a pro-M2 skewing effect on macrophage polarization.

Funding

  • Commercial Support