title: 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.
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; johannes.elvin@gu.se.
authors.forename: Johannes
authors.identifier: 0000-0002-9678-9020
authors.initials: J
authors.lastname: Elvin
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and Department of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Lisa
authors.initials: L
authors.lastname: Buvall
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Annika
authors.initials: A
authors.lastname: Lindskog Jonsson
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Anna
authors.initials: A
authors.lastname: Granqvist
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Emelie
authors.initials: E
authors.lastname: Lassén
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Lovisa
authors.initials: L
authors.lastname: Bergwall
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Nyström
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Börje
authors.initials: B
authors.lastname: Haraldsson
mesh_terms: D000818:Animals; D000963:Antimetabolites; D002374:Catalase / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D051379:Mice; D009401:Nephrosis / Q000139:chemically induced / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D050199:Podocytes / Q000187:drug effects*; D011692:Puromycin Aminonucleoside; D017382:Reactive Oxygen Species / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists* / Q000235:genetics; D022502:Stress Fibers / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000963:Antimetabolites; D017382:Reactive Oxygen Species; D044102:Receptor, Melanocortin, Type 1; D011692:Puromycin Aminonucleoside; D002374:Catalase; D020742:rhoA GTP-Binding Protein
keywords: actin stress fiber; melanocortin 1 receptor; oxidative stress; podocyte