Deficiency of Melanocortin 5 Receptor Exacerbates Proteinuria and Podocytopathy upon Glomerular Injury
- Glomerular Diseases: Podocyte Biology - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
- Chen, Bohan, The University of Toledo Department of Medicine, Toledo, Ohio, United States
- Ge, Yan, The University of Toledo Department of Medicine, Toledo, Ohio, United States
- Dworkin, Lance D., The University of Toledo Department of Medicine, Toledo, Ohio, United States
- Gong, Rujun, The University of Toledo Department of Medicine, Toledo, Ohio, United States
Converging evidence suggests that therapeutic targeting of nonsteroidogenic melanocortinergic pathways represents a novel strategy for treating proteinuric glomerulopathies. However, the type of melanocortin receptor (MCR) mediating this beneficial effect remains controversial and uncertain. Recent work indicates that MC5R is expressed in glomerular cells and MC5R signaling may be involved in glomerular pathobiology. This study examined the possible effect of MC5R ablation in nephrotoxic serum (NTS)-elicited podocytopathy.
NTS nephritis was induced in MC5R knockout (KO) mice and wild-type (WT) littermates. Additional WT mice received treatment with a highly selective MC5R agonist or vehicle before NTS injury. Proteinuria, podocyte injury and glomerular damage were evaluated early in the heterologous phase of NTS nephritis.
Despite no discernible phenotypes under physiological conditions, KO mice sustained exacerbated glomerulopathy upon NTS injury, as shown by heavier albuminuria. This was associated with worsened glomerular pathology, characterized by glomerular hypercellularity, swelling of glomerular endothelial cells, and fibrinoid necrosis of glomerular capillary tufts, although glomerular depositions of the glomerular basement membrane-reactive heterologous rabbit IgG and the C5b-9 membrane attack complex along the glomerular capillary loops were found to be comparable between the WT and KO groups after NTS insult. In parallel, KO mice exhibited more severe podocytopenia than WT mice after NTS injury, as evidenced by reduced numbers of WT-1 positive cells in glomeruli, as well as worsened podocyte injury, marked by loss of glomerular expression of podocyte homeostatic proteins such as podocin and synaptopodin. Conversely, to test if activation of MC5R signaling is sufficient to protect against NTS-elicited podocytopathy, WT mice with NTS nephritis were subjected to MC5R agonism by using a peptidomimetic selective agonist. This resulted in an attenuated proteinuria and an improved podocyte injury, as evidenced by preserved expression of podocyte marker proteins.
Our findings suggest that MC5R-mediated melanocortinergic signaling protects against proteinuria and podocytopathy upon glomerular injury, and may be harnessed as an actionable target for treating proteinuric glomerulopathies.
- NIDDK Support