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Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

Kishi S, Campanholle G, Gohil VM, Perocchi F, Brooks CR, Morizane R, Sabbisetti V, Ichimura T, Mootha VK, Bonventre JV - EBioMedicine (2015)

Bottom Line: Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria.Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001).Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Meclizine attenuates LDH and cytochrome c release during 2-DG and NaCN treatment of tubular epithelial cells.(A) LDH release from LLC-PK1 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 3). (B) LDH release from HK-2 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 7). (C) Western blot shows released cytochrome c from HK-2 cells after chemical anoxia in the presence or absence of meclizine pretreatment. (D) Quantitation of the band density of cytochrome c (n = 3). *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.
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f0030: Meclizine attenuates LDH and cytochrome c release during 2-DG and NaCN treatment of tubular epithelial cells.(A) LDH release from LLC-PK1 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 3). (B) LDH release from HK-2 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 7). (C) Western blot shows released cytochrome c from HK-2 cells after chemical anoxia in the presence or absence of meclizine pretreatment. (D) Quantitation of the band density of cytochrome c (n = 3). *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.

Mentions: To evaluate whether meclizine protected kidney tubular epithelial cells in vitro, cells were pretreated with meclizine 17 h prior to chemical anoxia induced by 1.5 mM of NaCN and 10 mM of 2-DG. A significant decrease of % LDH release in LLC-PK1 and HK-2 cells was observed in cells pretreated with 25 μM of meclizine when compared with cells pretreated with DMSO only (LLC-PK1 cells, 11.6 ± 3.2% vs 25.9 ± 1.5, p < 0.01, Fig. 5A, HK-2 cells, 27.0 ± 5.9 vs 47.6 ± 6.3%, p < 0.05, Fig. 5B, respectively). Furthermore meclizine pretreatment blocked the release of injury-associated cytochrome c from HK-2 cells exposed to chemical anoxia (Fig. 5C, D).


Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

Kishi S, Campanholle G, Gohil VM, Perocchi F, Brooks CR, Morizane R, Sabbisetti V, Ichimura T, Mootha VK, Bonventre JV - EBioMedicine (2015)

Meclizine attenuates LDH and cytochrome c release during 2-DG and NaCN treatment of tubular epithelial cells.(A) LDH release from LLC-PK1 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 3). (B) LDH release from HK-2 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 7). (C) Western blot shows released cytochrome c from HK-2 cells after chemical anoxia in the presence or absence of meclizine pretreatment. (D) Quantitation of the band density of cytochrome c (n = 3). *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4588407&req=5

f0030: Meclizine attenuates LDH and cytochrome c release during 2-DG and NaCN treatment of tubular epithelial cells.(A) LDH release from LLC-PK1 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 3). (B) LDH release from HK-2 cells treated with different concentrations of meclizine for 17 h followed by 2hr of chemical anoxia (n = 7). (C) Western blot shows released cytochrome c from HK-2 cells after chemical anoxia in the presence or absence of meclizine pretreatment. (D) Quantitation of the band density of cytochrome c (n = 3). *p < 0.05. Statistical significance was determined using one-way ANOVA followed by Tukey's post-hoc test. The columns and error bars are the mean ± SEM.
Mentions: To evaluate whether meclizine protected kidney tubular epithelial cells in vitro, cells were pretreated with meclizine 17 h prior to chemical anoxia induced by 1.5 mM of NaCN and 10 mM of 2-DG. A significant decrease of % LDH release in LLC-PK1 and HK-2 cells was observed in cells pretreated with 25 μM of meclizine when compared with cells pretreated with DMSO only (LLC-PK1 cells, 11.6 ± 3.2% vs 25.9 ± 1.5, p < 0.01, Fig. 5A, HK-2 cells, 27.0 ± 5.9 vs 47.6 ± 6.3%, p < 0.05, Fig. 5B, respectively). Furthermore meclizine pretreatment blocked the release of injury-associated cytochrome c from HK-2 cells exposed to chemical anoxia (Fig. 5C, D).

Bottom Line: Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria.Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001).Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media.

View Article: PubMed Central - PubMed

Affiliation: Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus