Deficiency of melanocortin 5 receptor exacerbates proteinuria and podocytopathy after glomerular injury

Background: 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. MC5R is one such receptor that is expressed in glomerular cells. This study examined the possible effect of MC5R knockout (KO) in nephrotoxic serum (NTS)-elicited podocytopathy. Methods: NTS nephritis was induced in MC5R 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. Results: Despite no discernible phenotype under physiological conditions, KO mice sustained exacerbated glomerulopathy early in the heterologous phase of NTS nephritis, as shown by heavier albuminuria. This was associated with worsened glomerular pathology, which was characterized by glomerular hypercellularity, swelling of glomerular endothelial cells, and fibrinoid necrosis