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Cited by 204Acute Kidney Injury ResearchMitochondrial Function and PathologyCardiac Ischemia and Reperfusion

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Protection against renal ischemia–reperfusion injury in vivo by the mitochondria targeted antioxidant MitoQ

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Dare, Anna J., Bolton, Eleanor A., Pettigrew, Gavin J., Bradley, J. Andrew, Saeb-Parsy, Kourosh, Murphy, Michael P.·2015·Redox Biology
DOI 10.1016/j.redox.2015.04.008PMC PMC4427662
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Abstract

Ischemia-reperfusion (IR) injury to the kidney occurs in a range of clinically important scenarios including hypotension, sepsis and in surgical procedures such as cardiac bypass surgery and kidney transplantation, leading to acute kidney injury (AKI). Mitochondrial oxidative damage is a significant contributor to the early phases of IR injury and may initiate a damaging inflammatory response. Here we assessed whether the mitochondria targeted antioxidant MitoQ could decrease oxidative damage during IR injury and thereby protect kidney function. To do this we exposed kidneys in mice to in vivo ischemia by bilaterally occluding the renal vessels followed by reperfusion for up to 24h. This caused renal dysfunction, measured by decreased creatinine clearance, and increased markers of oxidative damage. Administering MitoQ to the mice intravenously 15 min prior to ischemia protected the kidney from damage and dysfunction. These data indicate that mitochondrial oxidative damage contributes to kidney IR injury and that mitochondria targeted antioxidants such as MitoQ are potential therapies for renal dysfunction due to IR injury.

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Figures

Fig. 1 Accumulation of MitoQ within kidney mitochondria driven by the membrane potential. MitoQ accumulates within the cell driven by the plasma membrane potential (∆Ψp), then further accumulates within mitochondria driven by mitochondrial membrane potential (∆Ψm). In the mitochondrial matrix, MitoQ is reduced to the active antioxidant form, ubiquinol, by the respiratory chain preventing oxidative damage such as lipid peroxidation. Antioxidant activity generates the ubiquinone form, which is then recycled back to ubiquinol by the respiratory chain.
Fig. 1 Accumulation of MitoQ within kidney mitochondria driven by the membrane potential. MitoQ accumulates within the cell driven by the plasma membrane potential (∆Ψp), then further accumulates within mitochondria driven by mitochondrial membrane potential (∆Ψm). In the mitochondrial matrix, MitoQ is reduced to the active antioxidant form, ubiquinol, by the respiratory chain preventing oxidative damage such as lipid peroxidation. Antioxidant activity generates the ubiquinone form, which is then recycled back to ubiquinol by the respiratory chain.CC BY · PubMed Central
Fig. 2 Renal ischemia–reperfusion (IR) injury in a mouse model. (A) 45 min bilateral renal ischemia followed by reperfusion resulted in a significant increase in creatinine at 24 h compared to sham operated controls (laparotomy only) and 30 min ischemia (one-way ANOVA, p=<0.0001, with Bonferroni's post-testing between groups where ***p<0.001). (B) Intravenous administration of MitoQ 15 min prior to the onset of 45 min bilateral renal ischemia, significantly protected against kidney injury, as demonstrated by a lower creatinine at 24 h. Administration of decylTPP (dTPP) without the ubiquinone antioxidant moiety did not protect against IR injury. One-way ANOVA; p=<0.0001, with Bonferroni's post-testing between groups where *p<0.05, ***p<0.001. n=4–5/group. Data are means±SEM.
Fig. 2 Renal ischemia–reperfusion (IR) injury in a mouse model. (A) 45 min bilateral renal ischemia followed by reperfusion resulted in a significant increase in creatinine at 24 h compared to sham operated controls (laparotomy only) and 30 min ischemia (one-way ANOVA, p=<0.0001, with Bonferroni's post-testing between groups where ***p<0.001). (B) Intravenous administration of MitoQ 15 min prior to the onset of 45 min bilateral renal ischemia, significantly protected against kidney injury, as demonstrated by a lower creatinine at 24 h. Administration of decylTPP (dTPP) without the ubiquinone antioxidant moiety did not protect against IR injury. One-way ANOVA; p=<0.0001, with Bonferroni's post-testing between groups where *p<0.05, ***p<0.001. n=4–5/group. Data are means±SEM.CC BY · PubMed Central
Fig. 3 Oxidative damage to proteins and mtDNA following renal ischemia and 24 h reperfusion. (A) Protein carbonyl content in the kidney compared between sham operated groups, IR only and MitoQ+IR groups (one-way ANOVA; p=0.0046). Bonferroni's post-testing demonstrated a significant difference between the sham surgery and IR groups at the level of p<0.05, and between the IR and MitoQ+IR groups at the level of p<0.01. (B) mtDNA damage was measured using a quantitative PCR technique. The sham-operated control was normalized to one and relative amplification of mtDNA in the IR and MitoQ groups compared to this. There was a significant difference in mtDNA amplification between groups 24 h post IR injury (one-way ANOVA; p=<0.0001), suggesting significant damage to mtDNA had occurred. Bonferroni's post-testing demonstrated a significant difference between the sham surgery and IR groups at the level of p<0.001, and between the IR and MitoQ+IR groups at the level of p<0.01. n=4/group. *p<0.05, **p<0.01, ***p<0.001. Data are means±SEM.
Fig. 3 Oxidative damage to proteins and mtDNA following renal ischemia and 24 h reperfusion. (A) Protein carbonyl content in the kidney compared between sham operated groups, IR only and MitoQ+IR groups (one-way ANOVA; p=0.0046). Bonferroni's post-testing demonstrated a significant difference between the sham surgery and IR groups at the level of p<0.05, and between the IR and MitoQ+IR groups at the level of p<0.01. (B) mtDNA damage was measured using a quantitative PCR technique. The sham-operated control was normalized to one and relative amplification of mtDNA in the IR and MitoQ groups compared to this. There was a significant difference in mtDNA amplification between groups 24 h post IR injury (one-way ANOVA; p=<0.0001), suggesting significant damage to mtDNA had occurred. Bonferroni's post-testing demonstrated a significant difference between the sham surgery and IR groups at the level of p<0.001, and between the IR and MitoQ+IR groups at the level of p<0.01. n=4/group. *p<0.05, **p<0.01, ***p<0.001. Data are means±SEM.CC BY · PubMed Central
Fig. 4 Oxidative damage to the kidney at the end of ischemia and after 60 min reperfusion. (A) At the end of 45 min ischemia (left graph) there was no difference in protein carbonyl content between the sham group and the 45 min IR group or the MitoQ treated group (one-way ANOVA). After 60 min reperfusion (right graph) there was no significant difference between groups (one-way ANOVA). (b) mtDNA damage was measured using a quantitative PCR technique. As before, the sham operated control was normalized to one and relative amplification of mtDNA in the IR and MitoQ groups compared to this. There was no significant difference in mtDNA damage levels between the groups at the end of ischemia or after 60 min reperfusion (one-way ANOVA). n=4/group. Data are means±SEM.
Fig. 4 Oxidative damage to the kidney at the end of ischemia and after 60 min reperfusion. (A) At the end of 45 min ischemia (left graph) there was no difference in protein carbonyl content between the sham group and the 45 min IR group or the MitoQ treated group (one-way ANOVA). After 60 min reperfusion (right graph) there was no significant difference between groups (one-way ANOVA). (b) mtDNA damage was measured using a quantitative PCR technique. As before, the sham operated control was normalized to one and relative amplification of mtDNA in the IR and MitoQ groups compared to this. There was no significant difference in mtDNA damage levels between the groups at the end of ischemia or after 60 min reperfusion (one-way ANOVA). n=4/group. Data are means±SEM.CC BY · PubMed Central

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Metadata

Authors
Dare, A. J., Bolton, E. A., Pettigrew, G. J., Bradley, J. A., Saeb-Parsy, K., & Murphy, M. P.
Affiliations
  • MRC Mitochondrial Biology Unit (GB)
  • University of Cambridge (GB)
Corresponding author
Murphy, Michael P.
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2015-08
Volume
5
Pages
163-168
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2015.04.008
PMC
PMC4427662
OpenAlex
W2074937649
Cited by
202
References
44
Citations by year
2026: 10 · 2025: 22 · 2024: 11 · 2023: 17 · 2022: 18 · 2021: 25 · 2020: 26 · 2019: 20 · 2018: 17 · 2017: 11 · 2016: 16 · 2015: 7
FWCI
14.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Medical Research Council
  • NIHR Cambridge Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
Keywords
renal ischemia-reperfusion injury, MitoQ, mitochondria-targeted antioxidants, mitochondrial oxidative damage, acute kidney injury, renal dysfunction, renal protection, renal ischemia, oxidative stress
MeSH terms
Animals, Antioxidants, Creatinine, Kidney, Male, Mice, Inbred C57BL, Mitochondria, Organophosphorus Compounds, Ubiquinone, Reperfusion Injury, Oxidative Stress, Mice

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