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Abstract: FR-PO686

Inflammation and Calorie Restriction in Ercc1 PKO Mice

Session Information

Category: Glomerular Diseases

  • 1304 Glomerular Diseases: Podocyte Biology

Authors

  • Mandel, Amrei Maxi, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Blomberg, Linda, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Diefenhardt, Paul, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Braun, Fabian, III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Schermer, Bernhard, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Braehler, Sebastian, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Schumacher, Björn, CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Benzing, Thomas, Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Kurschat, Christine E., Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
Background

Terminally differentiated podocytes are highly susceptible to stress. Nucleotide excision repair (NER) genes are regulated in FSGS patient glomeruli. To study NER in podocytes, we generated a podocyte-specific Ercc1 knockout mouse (pko), which develops FSGS and shows activation of mTORC1 and inflammation, the latter shown here. Rapamycin treatment ameliorates the phenotype of Ercc1 pko mice. We present a calorie restriction study, known to inhibit mTORC1 and suppress inflammation and aging.

Methods

At 9 weeks of age, spleens and kidneys of Ercc1 pko and control mice were harvested and single-cell suspensions were prepared. T-cell and mononuclear phagocyte (MNP) populations were analyzed by flow cytometry using the BD LSRFortessa 2 cell analyzer. Immunohistochemistry for CD3 and MAC-2 was performed on kidneys of 12-week-old mice.
4-week-old Ercc1 pko mice were fed with 3.5 g standard diet over 4 weeks (CR). Two control groups were fed once daily with 4 g (SD) or ad libitum (AL). Histology as well as serum and urine analysis was performed at the end of the intervention period.

Results

9-week-old Ercc1 pko mice showed an increased leukocyte count, mainly represented by Th1 cells. Systemically, Th17 cells were significantly decreased in Ercc1 pko-spleens with no changes in other immune cell populations. However, at 12 weeks Ercc1 pko mice showed a strong increase in glomerular macrophages, whereas glomerular T-cell-counts were unchanged. Albuminuria and glomerulosclerosis in Ercc1 pko mice were significantly reduced after 4 weeks of calorie restriction in line with a decrease of glomerular pS6RP signal, a downstream target of mTORC1.

Conclusion

Ercc1 deficiency causes progeroid syndromes in humans and mice. Podocyte-specific deletion of Ercc1 leads to glomerulosclerosis and early death, accompanied by mTORC1 activation and inflammation. Calorie restriction and rapamycin ameliorated disease progression. Next to inhibition of mTORC1 and deceleration of aging, calorie restriction is known to reduce inflammation. We show that renal inflammation is increased in Ercc1 pko mice. Interestingly, T-helper cell infiltration proceeds MNP infiltration into the kidneys. This influx and activation of immune cells might be regulated by calorie restriction and thus might explain the attenuation in the intervention group.

Funding

  • Private Foundation Support