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Kidney Week

Abstract: FR-PO100

Mechanisms of Sex-Dependent Development of Acute Renal Failure - Insights from Preconditioning Experiments

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hoyer, Karla Johanna ruth, University of Cologne, Koeln, Germany
  • Späth, Martin, University of Cologne, Koeln, Germany
  • Kubacki, Torsten, University of Cologne, Koeln, Germany
  • Johnsen, Marc, University of Cologne, Koeln, Germany
  • Benzing, Thomas, University of Cologne, Koeln, Germany
  • Schermer, Bernhard, University of Cologne, Koeln, Germany
  • Burst, Volker Rolf, University of Cologne, Koeln, Germany
  • Mueller, Roman-Ulrich, University of Cologne, Koeln, Germany
Background

Experimental work on acute kidney failure in mice shows a clear sex distribution - the severity of renal failure in females is significantly lower than in males, however, the mechanisms are not clear. Interestingly, preconditioning (caloric restriction, hypoxia) prevents acute kidney injury (AKI) reliably. The aim of the work is to evaluate sex-specific mechanisms of the protective effect of caloric preconditioning.

Methods

14 week old male and female C57Bl6 wild-type mice underwent no preconditioning serving as a control group or four weeks of a calorie-restricted diet as a method of preconditioning prior to ischemia-reperfusion-injury (IRI). Afterwards, we compared control animals with animals after CR and males and females by phenotyping (histology, urea).

Results

IRI led to a pronounced kidney damage in males compared to a significantly lower damage in females. CR can completely prevent kidney failure in males. There is no significant improvement in the female mice compared to the untreated females. For further investigations, we performed a transcriptome analysis after preconditioning and were able to demonstrate the downregulation of a cytochrome P450 enzyme, Cyp4a12a, which is predominantly expressed in male mice. Cyp4a12a is necessary for the enzymatic production of 20-HETE, a derivative of arachidonic acid, which has an influence on renal regulation of blood pressure and volume retention. After the treatment of preconditioned animals with 20-HETE, the protective effect of caloric restriction can be abrogated. This suggests a possible relationship between the effect of preconditioning, sex, and a reduction of the concentration of 20-HETE.

Conclusion

The fact that female animals show a significant reduction of damage compared to males emphasizes the importance of the sex-specific analysis of the development of acute renal failure. In addition, we can report on the effect of caloric restriction and sex depending on the concentration of 20-HETE for the first time.