Melanocortin therapeutics, exemplified by adrenocorticotropic hormone, have a proven steroidogenic-independent anti-proteinuric and glomerular protective effect. The biological functions of melanocortins are mediated by melanocortin receptors (MCR), including MC1R, which recent studies have shown to protect against glomerular disease. However, the role of other MCRs like MC5R is unknown. Here, MC5R knockout exacerbated glomerulopathy in mice injured by adriamycin (ADR) or nephrotoxic serum (NTS), as demonstrated by increased albuminuria and podocyte injury. Conversely, selective MC5R agonism using a peptidomimetic agonist improved outcomes of glomerulopathies. Mechanistically, MC5R is expressed in glomerular podocytes. Reconstitution of MC5R in podocytes attenuated glomerular injury and proteinuria in MC5R knockout mouse models of glomerulopathies, indicating a direct podocyte protective effect. In vitro, MC5R agonism in primary wild-type podocytes attenuated ADR-elicited cytoskeleton disruption, hypermotility and apoptosis, associated with restored inhibitory phosphorylation of glycogen synthases kinase 3β (GSK3β), a signaling transducer downstream of MC5R and at the nexus of multiple podocytopathic pathways. In parallel, ADR-induced phosphorylation and activation of GSK3β substrates, such as paxillin and NFκB RelA/p65, were abrogated, leading to improved actin cytoskeleton integrity and diminished expression of mediators of podocyte injury, like MCP-1, B7-1 and Cathepsin L. This protective effect of MC5R agonism was blunted in wild-type podocytes expressing constitutively active GSK3β and was mimicked in MC5R knockout podocytes by ectopic expression of dominant negative GSK3β. Consistently in ADR-injured MC5R knockout mice, worsened podocytopathy was associated with enhanced GSK3β hyperactivity. These findings suggest that MC5R signaling protects against podocyte injury and may serve as a novel therapeutic target for glomerular diseases.
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