AP214, an analogue of alpha-melanocyte-stimulating hormone, ameliorates sepsis-induced acute kidney injury and mortality

Kidney Int. 2008 Jun;73(11):1266-74. doi: 10.1038/ki.2008.97. Epub 2008 Mar 19.

Abstract

Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. alpha-Melanocyte-stimulating hormone is a potent anti-inflammatory cytokine that inhibits many forms of inflammation including that with acute kidney injury. We tested whether a new alpha-melanocyte-stimulating hormone analogue (AP214), which has increased binding affinity to melanocortin receptors, improves sepsis-induced kidney injury and mortality using a cecal ligation and puncture mouse model. In the lethal cecal ligation-puncture model of sepsis, severe hypotension and bradycardia resulted and AP214 attenuated acute kidney injury of the lethal model with a bell-shaped dose-response curve. An optimum AP214 dose reduced acute kidney injury even when it was administered 6 h after surgery and it significantly improved blood pressure and heart rate. AP214 reduced serum TNF-alpha and IL-10 levels with a bell-shaped dose-response curve. Additionally; NF-kappaB activation in the kidney and spleen, and splenocyte apoptosis were decreased by the treatment. AP214 significantly improved survival in both lethal and sublethal models. We have shown that AP214 improves hemodynamic failure, acute kidney injury, mortality and splenocyte apoptosis attenuating pro- and anti-inflammatory actions due to sepsis.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Hemodynamics / drug effects
  • Hypotension / drug therapy
  • Hypotension / etiology
  • Hypotension / metabolism
  • Interleukin-10 / blood
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / etiology
  • Kidney Diseases / metabolism
  • Liver / drug effects
  • Mice
  • Mice, Inbred Strains
  • NF-kappa B / metabolism
  • Neutropenia / drug therapy
  • Neutropenia / etiology
  • Neutropenia / metabolism
  • Sepsis / complications*
  • Spleen / drug effects
  • Spleen / metabolism
  • Tumor Necrosis Factor-alpha / blood
  • alpha-MSH / analogs & derivatives*
  • alpha-MSH / pharmacology
  • alpha-MSH / therapeutic use

Substances

  • AP 214
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • alpha-MSH