Adrenocorticotropic hormone ameliorates acute kidney injury by steroidogenic-dependent and -independent mechanisms

Kidney Int. 2013 Apr;83(4):635-46. doi: 10.1038/ki.2012.447. Epub 2013 Jan 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / microbiology
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / prevention & control*
  • Adrenocorticotropic Hormone / pharmacology*
  • Albuminuria / metabolism
  • Albuminuria / prevention & control
  • Animals
  • Apoptosis / drug effects
  • Cecum / microbiology
  • Cecum / surgery
  • Cell Survival / drug effects
  • Cells, Cultured
  • Corticosterone / blood*
  • Cytoprotection
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gels
  • Glomerular Filtration Rate / drug effects
  • Kidney / drug effects*
  • Kidney / metabolism
  • Kidney / microbiology
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Tubular Necrosis, Acute / metabolism
  • Kidney Tubular Necrosis, Acute / pathology
  • Kidney Tubular Necrosis, Acute / prevention & control
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology
  • Ligation
  • Male
  • Mice
  • Punctures
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Melanocortin, Type 1 / agonists
  • Receptor, Melanocortin, Type 1 / genetics
  • Receptor, Melanocortin, Type 1 / metabolism
  • Time Factors
  • Transfection
  • Tumor Necrosis Factor-alpha
  • Up-Regulation

Substances

  • Gels
  • Receptor, Melanocortin, Type 1
  • Tumor Necrosis Factor-alpha
  • Adrenocorticotropic Hormone
  • Corticosterone