MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy
(2016) In Scientific Reports 6.- 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... (More)
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.
(Less)
- author
- Qiao, Yingjin ; Berg, Anna Lena LU ; Wang, Pei ; Ge, Yan ; Quan, Songxia ; Zhou, Sijie ; Wang, Hai ; Liu, Zhangsuo and Gong, Rujun
- organization
- publishing date
- 2016-06-08
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 6
- article number
- 27589
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:84974626018
- pmid:27270328
- wos:000377488000002
- ISSN
- 2045-2322
- DOI
- 10.1038/srep27589
- language
- English
- LU publication?
- yes
- id
- eab6b76c-4f84-4afd-a14b-679bc6895776
- date added to LUP
- 2017-01-24 11:00:11
- date last changed
- 2025-01-12 20:06:02
@article{eab6b76c-4f84-4afd-a14b-679bc6895776,
abstract = {{<p>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<sup>4</sup>, D-Phe<sup>7</sup> ]-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.</p>}},
author = {{Qiao, Yingjin and Berg, Anna Lena and Wang, Pei and Ge, Yan and Quan, Songxia and Zhou, Sijie and Wang, Hai and Liu, Zhangsuo and Gong, Rujun}},
issn = {{2045-2322}},
language = {{eng}},
month = {{06}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy}},
url = {{http://dx.doi.org/10.1038/srep27589}},
doi = {{10.1038/srep27589}},
volume = {{6}},
year = {{2016}},
}