Effects of melanocortin 1 receptor agonists in experimental nephropathies.
Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with α-melanocyte stimulating hormone (α-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease.
Department of Molecular and Clinical Medicine - Nephrology, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Annika
A
Lindskog Jonsson
Department of Molecular and Clinical Medicine - Nephrology, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Anna
A
Granqvist
Department of Molecular and Clinical Medicine - Nephrology, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Johannes
J
Elvin
Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, SUS Malmö, Sweden.
Martin E
ME
Johansson
Department of Molecular and Clinical Medicine - Nephrology, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Börje
B
Haraldsson
Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Jenny
J
Nyström
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy* / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists* / Q000378:metabolism
C523069:BMS-470539; D007093:Imidazoles; D044102:Receptor, Melanocortin, Type 1; D004317:Doxorubicin