Abstract: FR-PO986
Melanocortin 1 Receptor (MC1R) Deficiency Exacerbates Glomerular Injury and Proteinuria in the Autologous Phase of Nephrotoxic Serum (NTS) Nephritis
Session Information
- Pathology and Lab Medicine: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1601 Pathology and Lab Medicine: Basic
Authors
- Guan, Xuejing, University of Toledo Medical Center, Toledo, United States
- Zhou, Rong, Yangpu Hospital, Tongji University, Shanghai, China
- Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
- Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States
Background
The clinical effectiveness of melanocortin therapy with adrenocorticotropin in inducing remission of steroid-resistant nephrotic syndrome points to a steroidogenic-independent anti-proteinuric activity of melanocortins. However, which melanocortin receptor conveys this beneficial effect is controversial. A growing body of evidence suggests that activation of podocytic MC1R may convey a podocyte protective and anti-proteinuric effect. However, this paradigm seems inconclusive because MC1R agonist was seemingly ineffective in such nephrotoxic glomerulopathies as Adriamycin nephropathy. Moreover, how MC1R signaling is involved in immune-mediated glomerular diseases is unknown.
Methods
NTS nephritis was induced in mice with nonfunctional mutation of MC1R(e/e) and in wild-type (WT) mice by injection of rabbit NTS. Kidney function and renal injury were evaluated.
Results
Seven or 14 days after NTS injection during the autologous phase, e/e as compared with WT mice demonstrated an exacerbated kidney dysfunction and injury, as evidenced by higher serum creatinine levels, heavier proteinuria, and aggravated renal pathology, featured by glomerular hypercellularity, crescent formation, mesangial expansion, protein casts, and renal inflammation and fibrosis. Consistent with the worsened proteinuria, e/e mice displayed more severe podocyte injury, characterized by podocytopenia, marked by diminished WT-1 staining, and loss of podocyte markers like synaptopodin and podocin. Mechanistically, the aggravated renal disease in e/e mice was unlikely due to a sensitized response of the e/e kidney to injury, because 1 day after NTS insult during the heterologous phase, e/e mice developed albuminuria, podocytopathy and glomerular damage to a comparable extent as WT mice. Rather, deficiency of an MC1R-mediated non-kidney-autonomous or extra-renal mechanism may contribute. In support of this, e/e mice exhibited much more glomerular deposition of autologous anti-rabbit IgG together with the terminal complement complex C5b-9 along glomerular capillary loops than WT mice, despite the same degree of deposition of glomerular basement membrane-reactive rabbit IgG.
Conclusion
MC1R signaling protects against glomerular injury and proteinuria in immune-mediated glomerular disease via, at least in part, an immune modulatory effect.
Funding
- Commercial Support –