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Abstract: SA-PO449

A Bottom-Up Approach to Reduce Animal Numbers in Compound Screening Targeting Renal Regeneration After AKI

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Marschner, Julian A., Klinikum der Universitaet Muenchen, Munich, Germany
  • Zhao, Zhibo, Klinikum der Universitaet Muenchen, Munich, Germany
  • Platen, Louise Sophia, Klinikum der Universitaet Muenchen, Munich, Germany
  • Iwakura, Takamasa, Klinikum der Universitaet Muenchen, Munich, Germany
  • Holderied, Alexander, Klinikum der Universitaet Muenchen, Munich, Germany
  • Anders, Hans J., Klinikum der Universitaet Muenchen, Munich, Germany

Group or Team Name

  • AG Anders
Background

Developing new therapeutic approaches to improve kidney regeneration after injury remains a hurdle in translational nephrology, since 96% of in vivo identified drugs drop out due to lack of efficacy or safety concerns in humans. We developed a highly efficient, cost- and animal-saving bottom-up approach to screen compound libraries for their pro-regenerative capacity in tubular cells.

Methods

Using primary human renal progenitor cells (HPCs) and primary murine tubular epithelial cells (TECs) we tested 124 small molecules for their potential to induce hypertrophy and hyperplasia during homeostasis. We then exposed the cells to PBS and histones (mimicking ischemia/ injury) followed by a return to normal culture conditions (mimicking reperfusion), to test for the compounds pro-regenerative effects. Electric cell impedance sensing and selective progenitor cell expansion were used to monitor effects on wound healing and target cell response, respectively. Only those compounds that proved pro-regenerative in human and murine cells alike were tested in a mouse model of unilateral IRI.

Results

We identified RKI-1447 and SB-525334 in vitro/ ex vivo, and tested both substances in male C57BL/6J , 8-10 weeks of age, at 10 mg/kg every 2nd day for a duration of 3 weeks starting from day 3 after IRI. Both molecules reduced intrarenal mRNA markers of injury, inflammation, and fibrosis. A corresponding trend towards less parenchymal loss and fibrosis was observed in histology.

Conclusion

We were able to show, that an appropriate setup of in vitro and ex vivo experiments using meaningful biological material is suitable for (a) efficiently screening of compound libraries, (b) significantly reducing animal numbers used and (c) predicting outcome in vivo.

Bottom-up approach to identify pro-regenerative compounds, that have the capacity to enhance tubular cell healing after injury in human and murine tissue in vitro, ex vivo and in vivo.

Funding

  • Government Support - Non-U.S.