Kidney Week

Abstract: SA-PO085

Deciphering the Molecular Mechanisms Underlying Nephroprotection by Hypoxia-Signalling: A Comparative Analysis of Prolyl Hydroxylase Inhibition and Hypoxic Preconditioning

Session Information

• AKI: Mechanisms - Primary Injury and Repair - II
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Späth, Martin R., Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Martin R. Späth,

• Hoyer-Allo, Karla Johanna Ruth, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Karla Johanna Ruth Hoyer-Allo,

• Bohl, Katrin, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Katrin Bohl,

• Flamme, Ingo, Bayer Pharma AG, Wuppertal, Germany

Ingo Flamme,

• Koehler, Felix C., Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Felix C. Koehler,

• Grundmann, Franziska, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Franziska Grundmann,

• Debes, Cedric, CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

Cedric Debes,

• Beyer, Andreas, CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

Andreas Beyer,

• Schermer, Bernhard, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Bernhard Schermer,

• Benzing, Thomas, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Thomas Benzing,

• Burst, Volker Rolf, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Volker Rolf Burst,

• Mueller, Roman-Ulrich, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Germany, Cologne, Germany

Roman-Ulrich Mueller,

Background

Acute kidney injury (AKI) is one of the most common kidney diseases leading to increased morbidity and mortality. However, preventive or therapeutic strategies in the clinical setting are still missing. In animal models, AKI can be effectively prevented by preconditioning strategies – e.g. activating hypoxia signalling – that increase cellular stress resistance. Since translation of this approach by exposure to hypoxia (HP) is not feasible in the clinical setting, pharmacological strategies would be a favourable alternative. Therefore, inhibition of prolyl-hydroxylases (PHDi) and consecutive activation of hypoxia inducible factors (HIF) is an attractive strategy. Our aim was to confirm the protection by HP and PHDi in renal ischemia-reperfusion injury (IRI) and to characterize shared molecular patterns to identify novel therapeutic targets.

Methods

Male 14-week-old C57Bl6 wildtype mice were either treated with a PHD-inhibitor or by incremental exposure to hypoxia on three following days aiming for a similar induction of the HIF-target gene EPO to increase the comparability of both approaches. Afterwards all mice underwent a right nephrectomy and 40 min of contralateral renal IRI. In the following they were characterized functionally (e.g. by creatinine), histologically and by a transcriptomic and proteomic analysis of the right and left kidneys to unravel the molecular key players.

Results

Hypoxia and PHD-inhibition significantly ameliorated AKI 24 h after reperfusion. Histological analysis confirmed the protective effect of both strategies. The omics-analyses of the right kidneys revealed only little influence of HP and PHDi before damage. After damage, kidneys from HP and PHDi treated animals differed strongly from controls. There was only a limited overlap between both approaches which will allow for narrowing down the pathways and genes causally involved in organ protection.

Conclusion

Here, we confirmed the protective effect of HP and PHDi and performed the first comparative molecular phenotyping of kidneys treated with these strategies. Future studies will answer the question whether the genes and pathways identified can be modulated to prevent AKI.

Funding

• Commercial Support –