Augmenting autophagy to treat acute kidney injury during endotoxemia in mice

• Published in: PloS one Vol. 8; no. 7; p. e69520
• Main Authors: Howell, Gina M, Gomez, Hernando, Collage, Richard D, Loughran, Patricia, Zhang, Xianghong, Escobar, Daniel A, Billiar, Timothy R, Zuckerbraun, Brian S, Rosengart, Matthew R
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.07.2013; Public Library of Science (PLoS)
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Acute Kidney Injury - pathology; Age; Aging; Aminoimidazole Carboxamide - administration & dosage; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; Animal models; Animals; Autophagy; Autophagy - drug effects; Biology; Cecum; Cell death; Class III Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Endotoxemia; Endotoxemia - chemically induced; Endotoxemia - complications; Kidneys; Kinases; Lipopolysaccharides; Lipopolysaccharides - adverse effects; Male; Medicine; Mice; Older people; Phagocytosis; Pharmacology; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proteins; Renal failure; Renal function; Ribonucleotides - administration & dosage; Ribonucleotides - pharmacology; Rodents; Sepsis; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Surgery; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transplants & implants; United States > US; Pittsburgh Pennsylvania; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0069520

To determine that 1) an age-dependent loss of inducible autophagy underlies the failure to recover from AKI in older, adult animals during endotoxemia, and 2) pharmacologic induction of autophagy, even after established endotoxemia, is of therapeutic utility in facilitating renal recovery in aged mice. Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI). Academic research laboratory. C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age. Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg). Herein we report that diminished autophagy underlies the failure to recover renal function in older adult mice utilizing a murine model of LPS-induced AKI. The administration of the mTOR inhibitor temsirolimus, even after established endotoxemia, induced autophagy and protected against the development of AKI. These novel results demonstrate a role for autophagy in the context of LPS-induced AKI and support further investigation into like interventions that have potential to alter the natural history of disease.