Augmenting autophagy to treat acute kidney injury during endotoxemia in mice.
OBJECTIVE
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.


METHODS
Murine model of endotoxemia and cecal ligation and puncture (CLP) induced acute kidney injury (AKI).


METHODS
Academic research laboratory.


METHODS
C57Bl/6 mice of 8 (young) and 45 (adult) weeks of age.


METHODS
Lipopolysaccharide (1.5 mg/kg), Temsirolimus (5 mg/kg), AICAR (100 mg/kg).


RESULTS
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.


CONCLUSIONS
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.
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Gina M
GM
Howell
Hernando
H
Gomez
Richard D
RD
Collage
Patricia
P
Loughran
Xianghong
X
Zhang
Daniel A
DA
Escobar
Timothy R
TR
Billiar
Brian S
BS
Zuckerbraun
Matthew R
MR
Rosengart
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D000620:Aminoimidazole Carboxamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012265:Ribonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; C401859:temsirolimus; D058546:Class III Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C031143:AICA ribonucleotide; D020123:Sirolimus