Abstract: FR-PO159

Alterations of Mitochondrial Oxidative Metabolism in an Aging Model of Cisplatin Induced AKI

Session Information

  • Mitochondriacs and More
    November 03, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Mapuskar, Kranti A, University of Iowa, Iowa City, Iowa, United States
  • Zepeda-Orozco, Diana, Universiy of Iowa, Iowa City, Iowa, United States
  • Wen, Hsiang M., Universiy of Iowa, Iowa City, Iowa, United States
  • Mccormick, Michael L, University of Iowa, Iowa City, Iowa, United States
  • Schaeffer, Gilbert Van, University of Iowa, Iowa City, Iowa, United States
  • Sindler, Amy L., University of Iowa, Iowa City, Iowa, United States
  • Holanda, Danniele Gomes, University of Iowa Health Care, Iowa City, Iowa, United States
  • Rastogi, Prerna, University of Iowa Health Care, Iowa City, Iowa, United States
  • Spitz, Douglas R, University of Iowa, Iowa City, Iowa, United States
  • Allen, Bryan, University of Iowa, Iowa City, Iowa, United States
Background

Elderly patients have increased susceptibility to acute kidney injury (AKI). Increased oxidative stress and decreased antioxidant response may play a role in age associated AKI. The electron transport chain (ETC) complexes are a major metabolic site of reactive oxygen species (ROS) production in mammalian cells. In this study we hypothesized that aging is accompanied by abnormal mitochondrial oxidative metabolism that increases susceptibility to cisplatin induced AKI.

Methods

Young (4 months) and old (18 months) C57BL/6J mice received 10mg/kg intraperitoneal cisplatin injection vs. vehicle control. Blood urea nitrogen (BUN) and creatinine (Cr) measurements were obtained at baseline, 3, and 6 days post injection. Kidneys were harvested at 6 days to assess histological changes, mitochondrial oxidative metabolism, and antioxidant response

Results

Baseline renal function was not significantly different in young vs. old mice. Cisplatin caused significant renal function decline at 3 days in both groups. However, old cisplatin mice had less than 50% survival rate at 6 days compared to 100% survival in young mice. Control old mice demonstrated significant increased steady state levels of O2- and %GSH/GSSG, downregulation of mitochondrial ETC complex I, II, citrate synthase, and aconitase activities compared to young control mice. In both cisplatin groups, there was significant upregulation of complex I activity, with no significant change in complexes II-IV activity or citrate synthase activity compared to their respective vehicle controls suggesting that reverse electron transport (RET) may be a source of ROS production in cisplatin induced AKI. In cisplatin treated groups young mice had a significant upregulation of aconitase activity, which was not observed in old mice. Finally, in cisplatin treated old mice increased steady state levels of O2- were observed which was not seen in young mice

Conclusion

Our results support the hypothesis that aging is accompanied by alterations in oxidative mitochondrial metabolism that can be exacerbated by cisplatin injury. We hypothesize that RET through complex I may contribute to increased ROS production and enhanced kidney injury seen in older mice treated with cisplatin

Funding

  • Other NIH Support