Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation

Abstract

Drugs containing adrenocorticotropic hormone have been used as therapy for patients with nephrotic syndrome. We have previously shown that adrenocorticotropic hormone and a selective agonist for the melanocortin 1 receptor (MC1R) exert beneficial actions in experimental membranous nephropathy with reduced proteinuria, reduced oxidative stress, and improved glomerular morphology and function. Our hypothesis is that MC1R activation in podocytes elicits beneficial effects by promoting stress fibers and maintaining podocyte viability. To test the hypothesis, we cultured podocytes and used highly specific agonists for MC1R. Podocytes were subjected to the nephrotic-inducing agent puromycin aminonucleoside, and downstream effects of MC1R activation on podocyte survival, antioxidant defense, and cytoskeleton dynamics were studied. To increase the response and enhance intracellular signals, podocytes were transduced to overexpress MC1R. We showed that puromycin promotes MC1R expression in podocytes and that activation of MC1R promotes an increase of catalase activity and reduces oxidative stress, which results in the dephosphorylation of p190RhoGAP and formation of stress fibers through RhoA. In addition, MC1R agonists protect against apoptosis. Together, these mechanisms protect the podocyte against puromycin. Our findings strongly support the hypothesis that selective MC1R-activating agonists protect podocytes and may therefore be useful to treat patients with nephrotic syndromes commonly considered as podocytopathies.

MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy

“…identified MC1R as the dominant MCR in virtually all types of kidney parenchymal cells in humans and rats, including podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. However, in a following study, selective MC1R agonists barely induced any cAMP response in podocytes58. The doubt on podocyte expression of MC1R as well as MC1R-mediated podocyte protection was further accentuated by the contradictory effects of MC1R agonists on proteinuria and podocyte injury observed in different animal models of glomerulopathies59.…”

An Open-Label Pilot Study of Adrenocorticotrophic Hormone in the Treatment of IgA Nephropathy at High Risk of Progression

“…In addition, MC1R agonists protect against apoptosis and has been shown to lower proteinuria. 29,30 Systemic immunomodulation through MCR and anti-inflammatory effects on peripheral white blood cells through MCR 1, 3, and 5 may be other mechanisms by which ACTH exerts its effects. 31,32 ACTH gel was overall well-tolerated over 6 months, with reversible polycythemia in 1 patient and 6 infections, none resulting in hospitalization.…”

Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Identifies a Target for Podocyte Cytoskeleton Stabilization

“…In a previous study, we found that MC1R promotes increases stressfibers in podocytes and protects from PAN damage by activating RhoA 14 . PAN damage is a slow process (i.e.…”

“…First, we showed that activation of the epidermal growth factor receptor (EGFR) resulted in increase of Rac1 and loss of stressfibers in podocytes 13 . Secondly, we showed stress fiber protection from puromycin aminonucleoside (PAN) damage by MC1R activation resulting in regulation of the redox status of the cells and induction of stressfibers through RhoA 14 .…”