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

• Published in: Kidney international Vol. 73; no. 11; pp. 1266 - 1274
• Main Authors: Doi, K., Hu, X., Yuen, P.S.T., Leelahavanichkul, A., Yasuda, H., Kim, S.M., Schnermann, J., Jonassen, T.E.N., Frøkiær, J., Nielsen, S., Star, R.A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-06-2008; Nature Publishing
• Subjects: alpha-MSH - analogs & derivatives; alpha-MSH - pharmacology; alpha-MSH - therapeutic use; Animals; apoptosis; Bacterial diseases; Bacterial sepsis; Biological and medical sciences; Disease Models, Animal; hemodynamics; Hemodynamics - drug effects; Human bacterial diseases; Hypotension - drug therapy; Hypotension - etiology; Hypotension - metabolism; Infectious diseases; Interleukin-10 - blood; Kidney - drug effects; Kidney - metabolism; Kidney Diseases - drug therapy; Kidney Diseases - etiology; Kidney Diseases - metabolism; Kidneys; Liver - drug effects; Medical sciences; Mice; Mice, Inbred Strains; Nephrology. Urinary tract diseases; Neutropenia - drug therapy; Neutropenia - etiology; Neutropenia - metabolism; NF-kappa B - metabolism; Sepsis - complications; spleen; Spleen - drug effects; Spleen - metabolism; telemetry; Tumor Necrosis Factor-alpha - blood; Urinary system involvement in other diseases. Miscellaneous; apoptosis; telemetry; spleen; hemodynamics; Kidney disease; Spleen; Nephrology; Range finding; Urinary system disease; α-Melanocyte stimulating hormone; Acute kidney injury; Mortality; Epidemiology; Bacteremia; Urology; Infection; Sepsis syndrome; Pituitary hormone; Cell death; Analog; Bacteriosis; Hemodynamics; Apoptosis
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2008.97

Sepsis remains a serious problem in critically ill patients with the mortality increasing to over half when there is attendant acute kidney injury. α-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 α-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-α and IL-10 levels with a bell-shaped dose-response curve. Additionally; NF-κB 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.