Kidney Week

Abstract: FR-PO074

Cisplatin-Induced AKI: Preconditioning Protects by mRNA-Independent Proteome Alterations

Session Information

• AKI: Tubules, Metabolism, New Models
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Späth, Martin, Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Martin Späth,

• Bartram, Malte P., Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Malte P. Bartram,

• Palacio-Escat, Nicolàs, RWTH Aachen, Aachen, Germany

Nicolàs Palacio-Escat,

• Hoyer, Karla Johanna ruth, Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Karla Johanna ruth Hoyer,

• Schermer, Bernhard, Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Bernhard Schermer,

• Benzing, Thomas, Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Thomas Benzing,

• Burst, Volker Rolf, Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Volker Rolf Burst,

• Saez-Rodriguez, Julio, RWTH Aachen, Aachen, Germany

Julio Saez-Rodriguez,

• Huesgen, Pitter F., Forschungszentrum Juelich, Juelich, Germany

Pitter F. Huesgen,

• Mueller, Roman-Ulrich, Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Roman-Ulrich Mueller,

• Rinschen, Markus M., Department 2 of Internal Medicine, Renal Division; University of Cologne, Cologne, Germany

Markus M. Rinschen,

Background

Acute kidney injury is one of the most common kidney diseases, resulting in significantly increased morbidity and mortality. Unfortunately, strategies for prevention or causal treatment are lacking in routine clinical practice. During the last years it has been shown in animal models, that a number of preconditioning protocols have a protective effect.

Methods

We characterized two of these strategies - calorie restriction and hypoxic preconditioning - in a mouse model of cisplatin-induced acute kidney injury. To investigate the underlying mechanisms, we used multi-layered omic data (transcriptome, proteome, and N-degradome for measuring proteolytic activity) and functional parameters of preconditioned and non-preconditioned cisplatin-treated animals. These parameters were generated from identical animals and integrated bioinformatically.

Results

Both protocols significantly reduced cisplatin-induced acute kidney injury. Bioinformatic analysis revealed mRNA-independent proteomic changes affecting the extracellular compartment, mitochondrial function and tubular transporters. Interestingly, our analyzes showed a strong dissociation of protein and mRNA expression after cisplatin treatment. In the animal cohort, the degree of mRNA-protein dissociation showed a strong correlation (R> 0.95) with the degree of damage. N-degradome analysis revealed that most post-transcriptional changes were determined by Arg-specific proteolytic processing. This involved a characteristic cisplatin-induced complement activation, which was prevented by preconditioning. In addition, amyloid and acute phase proteins accumulated within the cortical parenchyma. Extensive analyzes of damage-associated molecular patterns (DAMPs) suggest that the transcription-independent deposition of serum amyloid P could play a key role in the contribution of the microenvironment to renal damage.

Conclusion

This study provides new insights into the pathogenesis of cisplatin-induced acute kidney injury and the molecular mechanisms that underly organ protection through preconditioning through multi-omic phenotype correlations.