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

Abstract

Melanocortin therapy by using adrenocorticotropic hormone (ACTH) or non-steroidogenic melanocortin peptides attenuates proteinuria and glomerular injury in experimental glomerular diseases and induces remission of nephrotic syndrome in patients with diverse glomerulopathies, even those resistant to steroids. The underlying mechanism remains elusive, but the role of melanocortin 1 receptor (MC1R) has been implicated and was examined here. Four patients with congenital red hair color and nephrotic syndrome caused by idiopathic membranous nephropathy or focal segmental glomerulosclerosis were confirmed by gene sequencing to bear dominant-negative MC1R mutations. Despite prior corticosteroid resistance, all patients responded to ACTH monotherapy and ultimately achieved clinical remission, inferring a steroidogenic-independent and MC1R-dispensable anti-proteinuric effect of melanocortin signaling. In confirmatory animal studies, the protective effect of [Nle4, D-Phe7]-α-melanocyte stimulating hormone (NDP-MSH), a potent non-steroidogenic pan-melanocortin receptor agonist, on the lipopolysaccharide elicited podocytopathy was completely preserved in MC1R-null mice, marked by reduced albuminuria and diminished histologic signs of podocyte injury. Moreover, in complementary in vitro studies, NDP-MSH attenuated the lipopolysaccharide elicited apoptosis, hypermotility and impairment of filtration barrier function equally in primary podocytes derived from MC1R-null and wild-type mice. Collectively, our findings suggest that melanocortin therapy confers a proteinuria reducing and podoprotective effect in proteinuric glomerulopathies via MC1R-independent mechanisms.

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

“…6 ). This could explain how patients with nephrotic syndrome carrying MC1R mutations impairing cAMP response can benefit from ACTH treatment 23 , by still having intact ERK1/2 signaling downstream of the MC1R.…”

Use of Repository Corticotropin Gel (Acthar) in Progressive Nephrotic Syndrome Secondary to Transplant Glomerulopathy: A Report of Three Cases

“…10,17 A number of studies suggest that the beneficial effect of melanocortin therapy is likely due to a direct action on podocytes. 10,18 Podocytes are a critical component of the glomerular filtration barrier controlling glomerular permeability, and podocytopathy is thought to underlie the massive proteinuria observed in diverse glomerular diseases. Melanocortin receptors are expressed in glomerular podocytes and it has been shown that receptor stimulation can reduce oxidative stress and improve glomerular morphology by diminishing podocyte apoptosis, injury, and loss in the remnant kidney animal model.…”

Adrenocorticotropic hormone analog use for podocytopathies

“…In contrast, Qiao et al 44 found a nonsteroidogenic melanocortin pan agonist to be equally effective in reducing proteinuria and ameliorating podocyte ultrastructural changes in MC1R -mutant and wild-type mice exposed to lipopolysaccharide or adriamycin. They also reported complete remissions with ACTH in two patients with mutated MC1R (congenital red hair) and refractory MN.…”

“…They also reported complete remissions with ACTH in two patients with mutated MC1R (congenital red hair) and refractory MN. 44 In a mouse model of experimental FSGS (adriamycin nephrosis), neither a MC1R agonist nor α-MSH had any beneficial effect on proteinuria or morphology. 43 In comparison, a significant beneficial effect of Acthar Gel was found in a model of secondary FSGS (nephron reduction), 45 even though corticosteroids are known to exacerbate injury in this model.…”