Journal
KIDNEY INTERNATIONAL
Volume 83, Issue 4, Pages 635-646Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ki.2012.447
Keywords
acute kidney injury; adrenocorticotropic hormone; apoptosis; melanocortin; melanocortin receptor; rodent
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Funding
- Questcor and National Institutes of Health [R01DK092485]
- National Natural Science Foundation of China [30900766]
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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 alpha-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. Kidney International (2013) 83, 635-646; doi:10.1038/ki.2012.447; published online 16 January 2013
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