{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T19:01:40Z","timestamp":1783105300065,"version":"3.54.6"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK114006"],"award-info":[{"award-number":["DK114006"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Clinical evidence indicates that the melanocortin peptide ACTH is effective in inducing remission of nephrotic glomerulopathies like minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), including those resistant to steroids. This suggests that a steroid-independent melancortinergic mechanism may contribute. However, the type of melanocortin receptor (MCR) that conveys this beneficial effect as well as the underlying mechanisms remain controversial. Burgeoning evidence suggests that MC5R is expressed in glomeruli and may be involved in glomerular pathobiology. This study aims to test the effectiveness of a novel highly selective MC5R agonist (MC5R-A) in puromycin aminonucleoside (PAN) nephrosis. Upon PAN injury, rats developed evident proteinuria on day 5, denoting an established nephrotic glomerulopathy. Following vehicle treatment, proteinuria continued to persist on day 14 with prominent histologic signs of podocytopathy, marked by ultrastructural glomerular lesions, including extensive podocyte foot process effacement. Concomitantly, there was loss of podocyte homeostatic markers, such as synaptopodin and podocin, and <jats:italic>de novo<\/jats:italic> expression of the podocyte injury marker desmin. Treatment with MC5R-A attenuated urine protein excretion and mitigated the loss of podocyte marker proteins, resulting in improved podocyte ultrastructural changes. <jats:italic>In vitro<\/jats:italic> in cultured podocytes, MC5R-A prevented the PAN-induced disruption of actin cytoskeleton integrity and apoptosis. MC5R-A treatment in PAN-injured podocytes also reinstated inhibitory phosphorylation and thus averted hyperactivity of GSK3\u03b2, a convergent point of multiple podocytopathic pathways. Collectively, pharmacologic activation of MC5R by using the highly selective small-molecule agonist is likely a promising therapeutic strategy to improve proteinuria and glomerular injury in protenuric nephropathies.<\/jats:p>","DOI":"10.3389\/fphys.2022.887641","type":"journal-article","created":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T14:10:46Z","timestamp":1654092646000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Pharmacological Melanocortin 5 Receptor Activation Attenuates Glomerular Injury and Proteinuria in Rats With Puromycin Aminonucleoside Nephrosis"],"prefix":"10.3389","volume":"13","author":[{"given":"Bohan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zubia","family":"Alam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance","family":"Dworkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rujun","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,1]]},"reference":[{"key":"B1","volume-title":"Common Patterns of Glomerular Gene Expression Profiles in Different Murine Models of Early Nephropathy","author":"Blutke","year":"2008"},{"key":"B2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/0021-9681(62)90100-5","article-title":"Corticosteroid Therapy of Glomerulonephritis and the Nephrotic Syndrome: a Review","volume":"15","author":"Adams","year":"1962","journal-title":"J. chronic Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1038\/ki.2014.428","article-title":"Fine-tuning of NF\u03baB by Glycogen Synthase Kinase 3\u03b2 Directs the Fate of Glomerular Podocytes upon Injury","volume":"87","author":"Bao","year":"2015","journal-title":"Kidney Int."},{"key":"B4","doi-asserted-by":"publisher","first-page":"15731","DOI":"10.1038\/s41598-018-34004-7","article-title":"Amplification of the Melanocortin-1 Receptor in Nephrotic Syndrome Identifies a Target for Podocyte Cytoskeleton Stabilization","volume":"8","author":"Bergwall","year":"2018","journal-title":"Sci. Rep."},{"key":"B5","first-page":"419","article-title":"Tumor Necrosis Factor Induces Glomerular Damage in the Rabbit","volume":"134","author":"Bertani","year":"1989","journal-title":"Am. J. Pathol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0158564","DOI":"10.1371\/journal.pone.0158564","article-title":"[Nle4, D-Phe7]-\u03b1-MSH Inhibits Toll-like Receptor (TLR)2- and TLR4-Induced Microglial Activation and Promotes a M2-like Phenotype","volume":"11","author":"Carniglia","year":"2016","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/2597079","article-title":"ACTH Treatment for Management of Nephrotic Syndrome: A Systematic Review and Reappraisal","volume":"2020","author":"Chakraborty","year":"2020","journal-title":"Int. J. Nephrol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1210\/er.2006-0034","article-title":"Studies on the Physiological Functions of the Melanocortin System","volume":"27","author":"Cone","year":"2006","journal-title":"Endocr. Rev."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e81812","DOI":"10.1371\/journal.pone.0081812","article-title":"A Novel Source of Cultured Podocytes","volume":"8","author":"Da Sacco","year":"2013","journal-title":"PLoS One"},{"key":"B10","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/s41573-021-00242-0","article-title":"The Glomerular Filtration Barrier: a Structural Target for Novel Kidney Therapies","volume":"20","author":"Daehn","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"B11","doi-asserted-by":"publisher","first-page":"F846","DOI":"10.1152\/ajprenal.00231.2015","article-title":"Melanocortin 1 Receptor Agonist Protects Podocytes through Catalase and RhoA Activation","volume":"310","author":"Elvin","year":"2016","journal-title":"Am. J. Physiology-Renal Physiology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1159\/000052600","article-title":"Increased Apoptosis in Acute Puromycin Aminonucleoside Nephrosis","volume":"9","author":"Fernandez","year":"2001","journal-title":"Nephron Exp. Nephrol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/bf00694922","article-title":"An Ultrastructural Study of the Effect of the Steroid in Puromycin Aminonucleoside Nephrosis Rats","volume":"405","author":"Fujiwara","year":"1984","journal-title":"Vichows Arch. A Pathol. Anat."},{"key":"B14","doi-asserted-by":"publisher","first-page":"E468","DOI":"10.1152\/ajpendo.00434.2002","article-title":"The Melanocortin System","volume":"284","author":"Gantz","year":"2003","journal-title":"Am. J. Physiology-Endocrinology Metabolism"},{"key":"B15","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/sj.bjp.0707115","article-title":"Selective Melanocortin MC4receptor Agonists Reverse Haemorrhagic Shock and Prevent Multiple Organ Damage","volume":"150","author":"Giuliani","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"B16","first-page":"449","article-title":"Involvement of Tumor Necrosis Factor and Platelet-Activating Factor in the Pathogenesis of Experimental Nephrosis in Rats","volume":"70","author":"G\u00f3mez-Chiarri","year":"1994","journal-title":"Laboratory investigation; a J. Tech. methods pathology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1053\/j.ackd.2013.09.004","article-title":"Leveraging Melanocortin Pathways to Treat Glomerular Diseases","volume":"21","author":"Gong","year":"2014","journal-title":"Adv. chronic kidney Dis."},{"key":"B18","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/nrneph.2011.190","article-title":"The Renaissance of Corticotropin Therapy in Proteinuric Nephropathies","volume":"8","author":"Gong","year":"2011","journal-title":"Nat. Rev. Nephrol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/s0014-2999(03)01322-0","article-title":"Characterization of Aliphatic, Cyclic, and Aromatic N-Terminally \"capped\" His-D-Phe-Arg-Trp-NH2 Tetrapeptides at the Melanocortin Receptors","volume":"462","author":"Holder","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1677\/jme-09-0161","article-title":"Melanocortins Induce Interleukin 6 Gene Expression and Secretion through Melanocortin Receptors 2 and 5 in 3T3-L1 Adipocytes","volume":"44","author":"Jun","year":"2010","journal-title":"J. Mol. Endocrinol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1002\/path.1711660313","article-title":"Cyclosporin Reduces Proteinuria in Rats with Aminonucleoside Nephrosis","volume":"166","author":"Kokui","year":"1992","journal-title":"J. Pathol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"4543","DOI":"10.1021\/bi00181a015","article-title":"Molecular Cloning of a Mouse Melanocortin 5 Receptor Gene Widely Expressed in Peripheral Tissues","volume":"33","author":"Labbe","year":"1994","journal-title":"Biochemistry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"4103","DOI":"10.4049\/jimmunol.1300182","article-title":"Both MC5r and A2Ar Are Required for Protective Regulatory Immunity in the Spleen of Post-experimental Autoimmune Uveitis in Mice","volume":"191","author":"Lee","year":"2013","journal-title":"J. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/path.4692","article-title":"The \u03b2 Isoform of GSK3 Mediates Podocyte Autonomous Injury in Proteinuric Glomerulopathy","volume":"239","author":"Li","year":"2016","journal-title":"J. Pathol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e87816","DOI":"10.1371\/journal.pone.0087816","article-title":"Effects of Melanocortin 1 Receptor Agonists in Experimental Nephropathies","volume":"9","author":"Lindskog Jonsson","year":"2014","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1097\/01.lab.0000017168.26718.16","article-title":"Podocyte-associated Molecules in Puromycin Aminonucleoside Nephrosis of the Rat","volume":"82","author":"Luimula","year":"2002","journal-title":"Lab. Invest."},{"key":"B27","first-page":"404","article-title":"Monocytes and Focal Glomerulosclerosis","volume":"61","author":"Magil","year":"1989","journal-title":"Lab. Invest."},{"key":"B28","doi-asserted-by":"publisher","first-page":"210","DOI":"10.23876\/j.krcp.2018.37.3.210","article-title":"Puromycin Aminonucleoside Triggers Apoptosis in Podocytes by Inducing Endoplasmic Reticulum Stress","volume":"37","author":"Min","year":"2018","journal-title":"Kidney Res. Clin. Pract."},{"key":"B29","doi-asserted-by":"publisher","first-page":"27589","DOI":"10.1038\/srep27589","article-title":"MC1R Is Dispensable for the Proteinuria Reducing and Glomerular Protective Effect of Melanocortin Therapy","volume":"6","author":"Qiao","year":"2016","journal-title":"Sci. Rep."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/7368389","article-title":"Activation of Melanocortin Receptors MC1and MC5Attenuates Retinal Damage in Experimental Diabetic Retinopathy","volume":"2016","author":"Rossi","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"B31","doi-asserted-by":"publisher","first-page":"e58162","DOI":"10.3791\/58162","article-title":"An Efficient Sieving Method to Isolate Intact Glomeruli from Adult Rat Kidney","author":"Rush","year":"2018","journal-title":"J. Vis. Exp."},{"key":"B32","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/ki.2012.447","article-title":"Adrenocorticotropic Hormone Ameliorates Acute Kidney Injury by Steroidogenic-dependent and -independent Mechanisms","volume":"83","author":"Si","year":"2013","journal-title":"Kidney Int."},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.5772\/61811","article-title":"Evaluation of the Glomerular Filtration Barrier by Electron Microscopy","volume-title":"Modern Electron Microscopy in Physical and Life Sciences","author":"Souza","year":"2016"},{"key":"B34","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1046\/j.1440-1711.2001.01022.x","article-title":"In Vitroinduction of CD25+CD4+regulatory T Cells by the Neuropeptide Alpha\u2010melanocyte Stimulating Hormone (\u03b1\u2010MSH)","volume":"79","author":"Taylor","year":"2001","journal-title":"Immunol. Cell Biol."},{"key":"B35","first-page":"53","article-title":"Melanocortin 5 Receptor and Ocular Immunity","volume":"52","author":"Taylor","year":"2006","journal-title":"Cell Mol. Biol. (Noisy-le-grand)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.3389\/fphys.2018.01475","article-title":"The Melanocortin MC5R as a New Target for Treatment of High Glucose-Induced Hypertrophy of the Cardiac H9c2 Cells","volume":"9","author":"Trotta","year":"2018","journal-title":"Front. Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1016\/j.kint.2020.05.052","article-title":"Global Transcriptomic Changes Occur in Aged Mouse Podocytes","volume":"98","author":"Wang","year":"2020","journal-title":"Kidney Int."},{"key":"B38","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1021\/acsmedchemlett.9b00198","article-title":"Single Nucleotide Polymorphisms in the Melanocortin His-Phe-Arg-Trp Sequences Decrease Tetrapeptide Potency and Efficacy","volume":"11","author":"Winget","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3831","DOI":"10.1007\/s00018-020-03511-0","article-title":"Melanocortin 5 Receptor Signaling Pathway in Health and Disease","volume":"77","author":"Xu","year":"2020","journal-title":"Cell. Mol. Life Sci."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.887641\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T14:10:53Z","timestamp":1654092653000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.887641\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,1]]},"references-count":39,"alternative-id":["10.3389\/fphys.2022.887641"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.887641","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,1]]},"article-number":"887641"}}