MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy.
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 [Nle(4), D-Phe(7)]-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.
Institute of Nephrology, Blood Purification Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.|Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Yingjin
Y
Qiao
Department of Nephrology, Lund University Hospital, Lund, Sweden.
Anna-Lena
AL
Berg
Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Pei
P
Wang
Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Yan
Y
Ge
Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Songxia
S
Quan
Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Sijie
S
Zhou
Department of Pathology, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Hai
H
Wang
Institute of Nephrology, Blood Purification Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Zhangsuo
Z
Liu
Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA.
Rujun
R
Gong
D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D006801:Humans; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D053486:Melanocortins / Q000008:administration & dosage* / Q000235:genetics; D051379:Mice; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D050199:Podocytes / Q000187:drug effects; D011507:Proteinuria / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000521:alpha-MSH / Q000008:administration & dosage
D053486:Melanocortins; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH; D000324:Adrenocorticotropic Hormone