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Kidney Week

Abstract: FR-PO150

Dissecting the Role of Tubular Manganese Superoxide Dismutase (MnSOD): Mitochondrial Oxidative Metabolism Disruption as an Adaptive Mechanism

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Vasquez Martinez, Gabriela, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Mayoral Andrade, Gabriel, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Li, Birong, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Jackson, Ashley R., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Mapuskar, Kranti A., University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Spitz, Douglas R., University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Allen, Bryan, University of Iowa Hospitals and Clinics, Iowa City, Iowa, United States
  • Zepeda-Orozco, Diana, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that catalyzes the conversion of superoxide (O2.-) to hydrogen peroxide (H2O2) in the mitochondrial matrix. Tubular MnSOD deletion results on renal histolgical abnormalities including tubular dilation, epithelial cell enlargement, and casts formation within the tubular lumen. However, there is no significant difference in serum creatinine or survival compared to WT mice suggesting that tubular MnSOD deletion leads to an adaptive response in mitochondrial metabolism that prevents renal dysfunction.

Methods

We developed a doxycycline-inducible pan-tubular MnSOD knock-out (Pax8rtTA-TetOcre-MnSODfl/fl, tMnSOD-KO). Mice were induced with doxycycline at 6 weeks of age, and seven months later we measued serum electrolytes and blood urea nitrogen (BUN). Transdermic glomerular filtration rate (tGFR) (WT=5 vs. KO=7) was evaluated prior to euthanasia. Whole kidney homogenates were used to measure mitochondrial electron transport chain (ETC) and tricarboxylic acid cycle (TCA) activities by spectrophotometric analysis and western blots (WT=11 vs. KO=5).

Results

No significant difference in serum electrolytes, tGFR, and BUN were noted between tMnSOD-KO and WT littermates. tMnSOD-KO and WT had no significant difference in citrate synthase activity, a surrogate marker of mitochondrial content. tMnSOD-KO kidneys demonstrated a decrease in ETC-Complex I and ETC-Complex II protein expression and activities. In contrast, ETC-Complex III and Aconitase activities were increased in the KO kidneys.

Conclusion

Tubular MnSOD deletion results in disruption of mitochondrial oxidative metabolism as well as TCA cycle enzymes 7 months post induction with preserved renal function. Future studies will provide insight into the implications of an adaptive response of mitochondrial oxidative metabolism in response to kidney injury.