Kidney Week

Abstract: PO1742

Melanocortin 5 Receptor (MC5R) Deficiency Aggravates Glomerular Injury and Proteinuria in the Autologous Phase of Nephrotoxic Serum (NTS) Nephritis

Session Information

• Glomerular Diseases: Vasculitis and TMA
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Chen, Bohan, University of Toledo Medical Center, Toledo, Ohio, United States

Bohan Chen,

• Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States

Lance D. Dworkin,

• Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States

Rujun Gong,

Background

The successful use of corticotropin in steroid-resistant nephrotic glomerulopathies suggests a unique proteinuria-reducing activity of adrenocorticotropic hormone that is steroidogenic-independent and may be attributable to its melanocortinergic activity. It remains uncertain which melanocortin receptor conveys this beneficial effect. Emerging evidence implicates MC5R signaling in the regulation of immune response. However, the role of MC5R in glomerular disease is unknown.

Methods

NTS nephritis was induced in MC5R knockout (MC5R^-/-) and wild-type (WT) mice. Kidney function, proteinuria and renal pathology were evaluated in the autologous phase.

Results

On 14 days after NTS injection in the autologous phase, MC5R^-/- as compared with WT mice exhibited an exacerbated kidney dysfunction and injury, as evidenced by higher serum creatinine levels, heavier proteinuria and aggravated renal pathology, featured by crescent formation, glomerular hypercellularity, mesangial expansion, protein casts in renal tubules, inflammatory infiltration in both glomeruli and tubulointerstitium and renal fibrosis. Consistent with the worsened proteinuria, MC5R^-/- mice displayed more severe podocyte injury and loss, as evidenced by diminished WT-1 staining and loss of homeostatic podocyte markers, like synaptopodin and podocin, as determined by immunohistochemistry staining and immunoblot analysis of isolated glomeruli. Mechanistically, although glomerular basement membrane-reactive rabbit IgG was found to deposit in glomeruli in both MC5R^-/- and WT mice to a comparable magnitude, MC5R^-/- mice demonstrated much more glomerular deposition of autologous anti-rabbit IgG together with enhanced fixation of the terminal complement complex C5b-9 along glomerular capillary loops in the autologous phase, suggesting that a potentiated humoral immune response to NTS antigen resulting from MC5R deficiency may contribute to the aggravated NTS nephritis.

Conclusion

MC5R signaling is essential for protection against glomerular injury and proteinuria in murine NTS nephritis via, at least in part, a regulatory effect on humoral immunity.

Funding

• NIDDK Support