Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.
Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Seiji
S
Kishi
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Gabriela
G
Campanholle
Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Vishal M
VM
Gohil
Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Fabiana
F
Perocchi
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Craig R
CR
Brooks
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ryuji
R
Morizane
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Venkata
V
Sabbisetti
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Takaharu
T
Ichimura
Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Vamsi K
VK
Mootha
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA ; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Joseph V
JV
Bonventre
D058186:Acute Kidney Injury / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D004983:Ethanolamines / Q000378:metabolism; D005690:Galactose / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D019194:Ischemic Preconditioning; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018374:LLC-PK1 Cells; D008297:Male; D008468:Meclizine / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D012966:Sodium Cyanide / Q000494:pharmacology; D013552:Swine; D015854:Up-Regulation / Q000187:drug effects
D004983:Ethanolamines; D020011:Protective Agents; D008468:Meclizine; C005448:phosphorylethanolamine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D003847:Deoxyglucose; D007770:L-Lactate Dehydrogenase; D012966:Sodium Cyanide; D005690:Galactose
Acute kidney injury; Glycolysis; Kennedy pathway; Mitochondria; Oxidative phosphorylation; Phosphoethanolamine