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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 inhibits mitochondrial respiration and reduces kidney IRI.(A) Oxygen consumption was measured in mitochondria isolated from kidneys of mice treated with two doses of 100mg/kg meclizine (Mec), 17 and 3 h before sacrifice. Traces are representative of three independent experiments, each performed in triplicate. Mitochondria (Mitos), ADP and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) were added at the indicated time points. Antimycin was used to inhibit respiration.(B and C) Real-time PCR analysis of Hmox1 and Nos2 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. (D) Representative images of Ksp-cadherin stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 200 ×, scale bar = 20 μm.(E) Quantification of Ksp-cadherin positive area. Original magnification 200 ×, scale bar = 20 μm.(F–I) Representative electron microscopic images of mitochondria in proximal tubular cells at 24 h after IRI obtained from vehicle or meclizine-treated kidneys 17 h before IRI. A red arrow indicates the brush borders and a white arrowhead indicates mitochondria. (J) Quantification of mitochondrial area. n = 3 sham, n = 3 to 8 IRI + Veh and IRI + meclizine, ****p < 0.0001; ***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 (B, C, E) or t test (J). The columns and error bars are the mean ± SEM. Scale bar = 2 μm.
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f0020: Meclizine inhibits mitochondrial respiration and reduces kidney IRI.(A) Oxygen consumption was measured in mitochondria isolated from kidneys of mice treated with two doses of 100mg/kg meclizine (Mec), 17 and 3 h before sacrifice. Traces are representative of three independent experiments, each performed in triplicate. Mitochondria (Mitos), ADP and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) were added at the indicated time points. Antimycin was used to inhibit respiration.(B and C) Real-time PCR analysis of Hmox1 and Nos2 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. (D) Representative images of Ksp-cadherin stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 200 ×, scale bar = 20 μm.(E) Quantification of Ksp-cadherin positive area. Original magnification 200 ×, scale bar = 20 μm.(F–I) Representative electron microscopic images of mitochondria in proximal tubular cells at 24 h after IRI obtained from vehicle or meclizine-treated kidneys 17 h before IRI. A red arrow indicates the brush borders and a white arrowhead indicates mitochondria. (J) Quantification of mitochondrial area. n = 3 sham, n = 3 to 8 IRI + Veh and IRI + meclizine, ****p < 0.0001; ***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 (B, C, E) or t test (J). The columns and error bars are the mean ± SEM. Scale bar = 2 μm.

Mentions: We tested meclizine as a potential therapeutic agent for kidney IRI based on its previously reported activity as mitochondrial respiration attenuating agent. While earlier work (Gohil et al., 2010, 2013) has clearly shown that meclizine attenuates mitochondrial respiration in an in vitro cell culture system, it is not known whether meclizine would attenuate respiration when administered to a whole organism. Therefore, to test the effect of meclizine on kidney respiration, mitochondria were isolated from the kidneys of mice pretreated with meclizine. Mice were treated with two doses of meclizine (100 mg/kg), 17 h and 3 h before sacrifice. Kidney mitochondria isolated from mice that received meclizine, had decreased O2 consumption after ADP addition and a further decrease after exposure to the uncoupling agent carbonyl cyanide 3-chlorophenylhydrazone (CCCP), when compared with kidney mitochondria isolated from vehicle-treated mice (Fig. 3A).


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 inhibits mitochondrial respiration and reduces kidney IRI.(A) Oxygen consumption was measured in mitochondria isolated from kidneys of mice treated with two doses of 100mg/kg meclizine (Mec), 17 and 3 h before sacrifice. Traces are representative of three independent experiments, each performed in triplicate. Mitochondria (Mitos), ADP and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) were added at the indicated time points. Antimycin was used to inhibit respiration.(B and C) Real-time PCR analysis of Hmox1 and Nos2 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. (D) Representative images of Ksp-cadherin stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 200 ×, scale bar = 20 μm.(E) Quantification of Ksp-cadherin positive area. Original magnification 200 ×, scale bar = 20 μm.(F–I) Representative electron microscopic images of mitochondria in proximal tubular cells at 24 h after IRI obtained from vehicle or meclizine-treated kidneys 17 h before IRI. A red arrow indicates the brush borders and a white arrowhead indicates mitochondria. (J) Quantification of mitochondrial area. n = 3 sham, n = 3 to 8 IRI + Veh and IRI + meclizine, ****p < 0.0001; ***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 (B, C, E) or t test (J). The columns and error bars are the mean ± SEM. Scale bar = 2 μm.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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f0020: Meclizine inhibits mitochondrial respiration and reduces kidney IRI.(A) Oxygen consumption was measured in mitochondria isolated from kidneys of mice treated with two doses of 100mg/kg meclizine (Mec), 17 and 3 h before sacrifice. Traces are representative of three independent experiments, each performed in triplicate. Mitochondria (Mitos), ADP and carbonyl cyanide m-chlorophenyl hydrazone (CCCP) were added at the indicated time points. Antimycin was used to inhibit respiration.(B and C) Real-time PCR analysis of Hmox1 and Nos2 mRNA in sham, vehicle and meclizine pretreated mice at 48 h after IRI. (D) Representative images of Ksp-cadherin stained kidneys from sham, vehicle and meclizine pretreated mice at 48 h after IRI. Original magnification 200 ×, scale bar = 20 μm.(E) Quantification of Ksp-cadherin positive area. Original magnification 200 ×, scale bar = 20 μm.(F–I) Representative electron microscopic images of mitochondria in proximal tubular cells at 24 h after IRI obtained from vehicle or meclizine-treated kidneys 17 h before IRI. A red arrow indicates the brush borders and a white arrowhead indicates mitochondria. (J) Quantification of mitochondrial area. n = 3 sham, n = 3 to 8 IRI + Veh and IRI + meclizine, ****p < 0.0001; ***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 (B, C, E) or t test (J). The columns and error bars are the mean ± SEM. Scale bar = 2 μm.
Mentions: We tested meclizine as a potential therapeutic agent for kidney IRI based on its previously reported activity as mitochondrial respiration attenuating agent. While earlier work (Gohil et al., 2010, 2013) has clearly shown that meclizine attenuates mitochondrial respiration in an in vitro cell culture system, it is not known whether meclizine would attenuate respiration when administered to a whole organism. Therefore, to test the effect of meclizine on kidney respiration, mitochondria were isolated from the kidneys of mice pretreated with meclizine. Mice were treated with two doses of meclizine (100 mg/kg), 17 h and 3 h before sacrifice. Kidney mitochondria isolated from mice that received meclizine, had decreased O2 consumption after ADP addition and a further decrease after exposure to the uncoupling agent carbonyl cyanide 3-chlorophenylhydrazone (CCCP), when compared with kidney mitochondria isolated from vehicle-treated mice (Fig. 3A).

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