Intercepting the complement amplification loop through podocyte MC5R signaling ameliorates membranous nephropathy

Melanocortin therapy has demonstrated potential in improving membranous nephropathy in human patients. The underlying mechanisms remain unclear. Here, in a heterologous mouse model of THSD7A-associated membranous nephropathy, various melanocortin agents, including repository corticotropin injection, the nonsteroidogenic pan-melanocortin receptor agonist NDP-MSH, and the selective melanocortin 5 receptor (MC5R) agonist PG-901, attenuated proteinuria, and ameliorated glomerulopathy. In contrast, MC5R knockout exacerbated membranous nephropathy, while abolishing the beneficial effects of melanocortins. Mechanistically, MC5R expression was evident in podocytes in wild-type mice, and podocyte MC5R appears to protect against membranous nephropathy, as demonstrated by its necessity for melanocortin protection in cultured podocytes, and restoration of melanocortin therapeutic efficacy in MC5R knockout mouse after podocyte-specific reconstitution of MC5R. Furthermore, glomerular fixation of C5b-9 and C3 was diminished by MC5R agonism but enhanced by MC5R knockout, despite comparable glomerular deposition of the heterologous nephritogenic antibody and activation of C4. Comprehensive complement cascade analysis revealed that this anti-complement effect of MC5R signaling stems from an inhibition of podocyte expression of complement factors B and D, critical regulators of the complement amplification loop, involving a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Ergo, MC5R-mediated interception of the complement amplification loop in podocytes may serve as a novel therapeutic target for membranous nephropathy.