NDP-MSH attenuates kidney damage and proteinuria in experimental FSGS via a podocyte-specific, non-MC1R-mediated pathway.

The clinical use of adrenocorticotropin for steroid-resistant nephrotic syndrome suggests that melanocortins have anti-proteinuric effects separate from their steroid-producing actions. However, the specific melanocortin receptors (MCRs) and mechanisms—whether systemic or localized to podocytes (specialized kidney cells)—responsible for this benefit are unknown. This knowledge gap hinders the development of more targeted therapies for glomerular diseases like focal segmental glomerulosclerosis (FSGS), where podocyte injury leads to protein leakage into the urine (proteinuria) and kidney dysfunction. This study investigates if a pan-MCR agonist can directly protect podocytes and which receptor subtype, particularly MC1R, is essential for this effect.

The study used a mouse model of Adriamycin-induced focal segmental glomerulosclerosis (FSGS). Wild-type (WT) and MC1R-null mice were subjected to Adriamycin insult to induce kidney injury. One group received treatment with NDP-MSH, a potent, non-steroidogenic pan-MCR agonist. Researchers assessed kidney function, proteinuria, and glomerular pathology, including podocyte injury markers like podocin, synaptopodin, and desmin, using electron microscopy. Additionally, they conducted in vitro experiments on primary podocytes from both WT and MC1R-null mice, exposing them to Adriamycin with and without NDP-MSH to evaluate direct cellular effects on apoptosis, cytoskeleton arrangement, and hypermotility.

In vivo, Adriamycin insult caused severe proteinuria, kidney dysfunction, and FSGS in wild-type mice. Treatment with NDP-MSH significantly attenuated all these pathological findings, including the loss of podocin and synaptopodin, podocytopenia, and foot process effacement. Surprisingly, MC1R deficiency did not worsen the Adriamycin-induced injury, and the protective effects of NDP-MSH were fully preserved in MC1R-null mice, indicating MC1R is not essential for the therapeutic action. The in vitro experiments confirmed a direct protective effect on podocytes.

NDP-MSH mitigated Adriamycin-inflicted cytopathic signs in primary podocytes, including apoptosis, loss of podocyte markers, de novo expression of the injury marker desmin, actin cytoskeleton derangement, and podocyte hypermotility. This podoprotective activity was fully preserved in MC1R-null podocytes. Mechanistic analysis revealed that MC1R expression was negligible in podocytes but was predominantly found in glomerular endothelial cells, further supporting a non-MC1R-mediated protective pathway within the podocytes themselves.