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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

Pretreatment with meclizine protects the kidney against IRI.(A) Scheme illustrating the strategy for the dose–response experiments. (B) Serum creatinine levels at 24 h after IRI, in animals pretreated 17 and 3 h before IRI with vehicle or various doses of meclizine. (C) Scheme illustrating the strategy comparing effectiveness of treatment at various times prior to IRI. (D) Serum creatinine levels at 24 h after IRI, in animals pretreated with a one-time injection of meclizine at different time-points before IRI. (E) BUN levels at 24 h after IRI in mice pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). (F) Real-time PCR analysis of KIM-1 mRNA (Havcr1) in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Mice were pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 4) and IRI + meclizine (n = 4). (G) Representative images after hematoxylin and eosin (H & E) and Periodic acid-Schiff (PAS) staining of tissue taken 48 h after IRI. Original magnification 200 ×, scale bar = 100 μm. (H) Tubular necrosis was semi-quantified by scoring H&E stained slides. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). ***p < 0.001; **p < 0.01 and *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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f0010: Pretreatment with meclizine protects the kidney against IRI.(A) Scheme illustrating the strategy for the dose–response experiments. (B) Serum creatinine levels at 24 h after IRI, in animals pretreated 17 and 3 h before IRI with vehicle or various doses of meclizine. (C) Scheme illustrating the strategy comparing effectiveness of treatment at various times prior to IRI. (D) Serum creatinine levels at 24 h after IRI, in animals pretreated with a one-time injection of meclizine at different time-points before IRI. (E) BUN levels at 24 h after IRI in mice pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). (F) Real-time PCR analysis of KIM-1 mRNA (Havcr1) in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Mice were pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 4) and IRI + meclizine (n = 4). (G) Representative images after hematoxylin and eosin (H & E) and Periodic acid-Schiff (PAS) staining of tissue taken 48 h after IRI. Original magnification 200 ×, scale bar = 100 μm. (H) Tubular necrosis was semi-quantified by scoring H&E stained slides. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). ***p < 0.001; **p < 0.01 and *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: Statistical analysis was performed using Prism 6.0 (GraphPad Software Inc.). Evaluation of the data was carried out using the unpaired two-tailed t test when two groups were compared or one-way Analysis of Variance (ANOVA) followed by Tukey's post-test when multiple groups were compared. A p value lower than 0.05 was considered to be significant. Statistical power analyses were performed to evaluate sample numbers necessary for the main group comparisons reflected in Fig. 1B and D. Animal number in each group was chosen to have a statistical power higher than 0.80 (Cohen, 1992; Faul et al., 2007, 2009). When not specifically stated results are presented as means of at least three independent experiments and error bars indicate ± SEM.


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)

Pretreatment with meclizine protects the kidney against IRI.(A) Scheme illustrating the strategy for the dose–response experiments. (B) Serum creatinine levels at 24 h after IRI, in animals pretreated 17 and 3 h before IRI with vehicle or various doses of meclizine. (C) Scheme illustrating the strategy comparing effectiveness of treatment at various times prior to IRI. (D) Serum creatinine levels at 24 h after IRI, in animals pretreated with a one-time injection of meclizine at different time-points before IRI. (E) BUN levels at 24 h after IRI in mice pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). (F) Real-time PCR analysis of KIM-1 mRNA (Havcr1) in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Mice were pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 4) and IRI + meclizine (n = 4). (G) Representative images after hematoxylin and eosin (H & E) and Periodic acid-Schiff (PAS) staining of tissue taken 48 h after IRI. Original magnification 200 ×, scale bar = 100 μm. (H) Tubular necrosis was semi-quantified by scoring H&E stained slides. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). ***p < 0.001; **p < 0.01 and *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

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

f0010: Pretreatment with meclizine protects the kidney against IRI.(A) Scheme illustrating the strategy for the dose–response experiments. (B) Serum creatinine levels at 24 h after IRI, in animals pretreated 17 and 3 h before IRI with vehicle or various doses of meclizine. (C) Scheme illustrating the strategy comparing effectiveness of treatment at various times prior to IRI. (D) Serum creatinine levels at 24 h after IRI, in animals pretreated with a one-time injection of meclizine at different time-points before IRI. (E) BUN levels at 24 h after IRI in mice pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). (F) Real-time PCR analysis of KIM-1 mRNA (Havcr1) in sham, vehicle and meclizine pretreated mice at 48 h after IRI. Mice were pretreated 17 h before IRI with a one-time injection of 100 mg/kg of meclizine or vehicle. Sham (n = 3), IRI + Veh (n = 4) and IRI + meclizine (n = 4). (G) Representative images after hematoxylin and eosin (H & E) and Periodic acid-Schiff (PAS) staining of tissue taken 48 h after IRI. Original magnification 200 ×, scale bar = 100 μm. (H) Tubular necrosis was semi-quantified by scoring H&E stained slides. Sham (n = 3), IRI + Veh (n = 8) and IRI + meclizine (n = 8). ***p < 0.001; **p < 0.01 and *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: Statistical analysis was performed using Prism 6.0 (GraphPad Software Inc.). Evaluation of the data was carried out using the unpaired two-tailed t test when two groups were compared or one-way Analysis of Variance (ANOVA) followed by Tukey's post-test when multiple groups were compared. A p value lower than 0.05 was considered to be significant. Statistical power analyses were performed to evaluate sample numbers necessary for the main group comparisons reflected in Fig. 1B and D. Animal number in each group was chosen to have a statistical power higher than 0.80 (Cohen, 1992; Faul et al., 2007, 2009). When not specifically stated results are presented as means of at least three independent experiments and error bars indicate ± SEM.

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