Abstract: TH-PO304

Cisplatin-Induced AKI: Proteomic and Transcriptomic Analysis Unravels Molecular Correlates of the Protective Effect of Caloric Restriction and Hypoxic Preconditioning

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Späth, Martin, University of Cologne, Cologne, Germany
  • Bartram, Malte P., University of Cologne, Cologne, Germany
  • Hoyer, Karla Johanna ruth, University of Cologne, Cologne, Germany
  • Burst, Volker Rolf, University of Cologne, Cologne, Germany
  • Mueller, Roman-Ulrich, University of Cologne, Cologne, Germany
  • Rinschen, Markus M., University of Cologne, Cologne, Germany
Background


Acute kidney injury (AKI) is a strong risk factor for cardiovascular morbidity and chronic kidney disease, but causal treatment is still missing. In animal models it can be reduced by preconditioning protocols, but little is known about the underlying molecular mechanisms. We aimed for identifying these in two modes of preconditioning.

Methods

20-week-old C57Bl6-wildtype mice were treated intraperitoneally with cisplatin comparing mice preconditioned by hypoxia (HP) or caloric restriction (CR) to controls. All mice were phenotyped (plasma creatinine, blood urea nitrogen, histology) and a proteomic and transcriptomic analysis of the renal cortex was done. Additionally we analyzed the whole-cell proteome in cultured proximal tubular cells after cisplatin-damage.

Results

CR completely prevented AKI and HP showed a significant damage reduction. Cisplatin-administration led to a significant increase of extracellular matrix-, complement- and MHC-proteins, in addition to several known markers for AKI. Kinases, receptors and ubiquitin ligases, potential therapeutic targets, were increased in cisplatin-treated kidneys. Brush-border and transport proteins were reduced. Treatment of tubular cells showed that the above mentioned findings can be partly recapitulated in-vitro.
The integration of the proteomic with the transcriptomic data showed the largest posttranscriptional changes in mice only treated with cisplatin. The proteomic data was correlated with plasma kidney function values. A positive correlation of extracellular proteins and a negative correlation of brush-border proteins with the damage were shown. A bioinformatical integration of a text-mining-analysis with the correlation-analysis led to a prediction of new “damage-associated-molecular-patterns” partially strongly correlating (R>0.8) with the kidney function. Proteins related to fatty acid synthesis were increased in kidneys of calorie restricted animals, suggesting that increased renal fatty acid synthesis may be involved in renoprotection.

Conclusion

In conclusion these data shows mechanistic insights of the protective effect of preconditioning in cisplatin-induced AKI and the potential of proteome-phenotype-correlations in nephrological basic science.