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Abstract: SA-PO273

Metabolomics of Drug-Induced Mitochondrial Biogenesis in Aged Mice Kidneys

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Thompson, Austin D., The University of Arizona College of Pharmacy, Tucson, Arizona, United States
  • Janda, Jaroslav, The University of Arizona College of Pharmacy, Tucson, Arizona, United States
  • Schnellmann, Rick G., The University of Arizona College of Pharmacy, Tucson, Arizona, United States
Background

Mitochondrial dysfunction is important in the aging process of many organs. We have shown that MC16, a drug candidate, induces mitochondrial biogenesis (MB) in mouse renal cortices and improves renal function in response to acute kidney injury. Thus, we hypothesized that stimulation of MB in aged mouse kidneys would improve global metabolomics in the kidney cortex.

Methods

Aged 22-month-old male C57B/6J mice were administered 1.0mg/kg MC16 or normal saline every other day over 21 days (n=8-9/group). Seven-month-old controls were administered normal saline every other day over 21 days (n=7). Kidneys were harvested and snap frozen in liquid nitrogen. Cortical biopsies were analyzed by Metabolon via multi-mass spectrometry. After mass normalization, log-transformation, and imputation, Welch’s two-sample t-test was used to identify metabolites that differed significantly between treatment groups. A p-value of p≤0.05 and a false discovery rate of q<0.10 were used to identify global metabolite changes and correct for multiple comparisons.

Results

In total, the dataset of detected metabolites consisted of 1,010 biochemicals (BCs). Of these, 441 were statistically different in saline-treated old mice compared to young control mice, with 276 BCs increased and 165 BCs decreased. 140 BCs were statistically different in the MC16-treated old mice group compared to the saline-treated old mice group, with 72 BCs increased and 68 BCs decreased. Saline-treated old mice had reduced 1,5-anhydroglucitol and elevated glucose-6-phosphate, fructose-6-phosphate, and dihydroxyacetone phosphate compared to young control mice, indicative of enhanced glycolysis. Conversely, MC16-treated old mice had no statistical changes in glycolysis metabolites compared to young control mice. While both groups had elevated carnitine levels, MC16-treated old mice derived most of their carnitines from fatty acid metabolism, indicative of impaired fatty acid metabolism in the saline-treated old mice group.

Conclusion

These data reveal that global metabolomics can be utilized to identify various age-related kidney metabolic alterations within the renal cortices of mice. This approach will allow us to identify and monitor age-/disease- related metabolic changes in the renal cortex of mice to evaluate potential pharmacological agents that may alter/blunt the progression of renal dysfunction in future studies.

Funding

  • Other NIH Support