title: Adrenocorticotropic hormone ameliorates acute kidney injury by steroidogenic-dependent and -independent mechanisms.
abstract: Adrenocorticotropic hormone (ACTH) has a renoprotective effect in chronic kidney disease; however, its effect on acute kidney injury (AKI) remains unknown. In a rat model of tumor necrosis factor (TNF)-induced AKI, we found that ACTH gel prevented kidney injury, corrected acute renal dysfunction, and improved survival. Morphologically, ACTH gel ameliorated TNF-induced acute tubular necrosis, associated with a reduction in tubular apoptosis. While the steroidogenic response to ACTH gel plateaued, the kidney-protective effect continued to increase at even higher doses, suggesting steroid-independent mechanisms. Of note, ACTH also acts as a key agonist of the melanocortin system, with its cognate melanocortin 1 receptor (MC1R) abundantly expressed in renal tubules. In TNF-injured tubular epithelial cells in vitro, ACTH reinstated cellular viability and eliminated apoptosis. This beneficial effect was blunted in MC1R-silenced cells, suggesting that this receptor mediates the anti-apoptotic signaling of ACTH. Moreover, ACTH gel protected mice against cecal ligation puncture-induced septic AKI better than α-melanocyte-stimulating hormone: a protein equal in biological activity to ACTH except for steroidogenesis. Thus, ACTH has additive renoprotective actions achieved by both steroid-dependent mechanisms and MC1R-directed anti-apoptosis. ACTH may represent a novel therapeutic strategy to prevent or treat AKI.
authors: Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown Medical School, Providence, Rhode Island 02903, USA.
authors: Jin
authors: J
authors: Si
authors: Yan
authors: Y
authors: Ge
authors: Shougang
authors: S
authors: Zhuang
authors: Li Juan
authors: LJ
authors: Wang
authors: Shan
authors: S
authors: Chen
authors: Rujun
authors: R
authors: Gong
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000419:Albuminuria / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002432:Cecum / Q000382:microbiology / Q000601:surgery; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003345:Corticosterone / Q000097:blood*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005782:Gels; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000503:physiopathology; D007683:Kidney Tubular Necrosis, Acute / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008026:Ligation; D008297:Male; D051379:Mice; D011677:Punctures; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D044102:Receptor, Melanocortin, Type 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation
chemical_list: D005782:Gels; D044102:Receptor, Melanocortin, Type 1; D014409:Tumor Necrosis Factor-alpha; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone