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Abstract: FR-PO599

Atypical Chemokine Receptor 4 Is Expressed in Kidney Glomeruli and Mitigates the Severity of Experimental Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Artinger, Katharina, Clinical Division of Nephrology, Medical University of Graz, Graz, Austria
  • Hub, Elin, Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
  • Kirsch, Alexander H., Clinical Division of Nephrology, Medical University of Graz, Graz, Austria
  • Eller, Philipp, Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
  • Rosenkranz, Alexander R., Clinical Division of Nephrology, Medical University of Graz, Graz, Austria
  • Eller, Kathrin, Clinical Division of Nephrology, Medical University of Graz, Graz, Austria
  • Rot, Antal, Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
Background

Besides ligating their cognate GPCRs, chemokines importantly interact with atypical chemokine receptors (ACKRs) that are characterised by mostly non-overlapping microanatomical expression and distinctive ligand specificities. ACKR4 is expressed in primary and secondary lymphoid organs, where it is involved in regulating cell migratory steps required for optimal immune responses and furthermore by a hugely varying types of cells in multiple parenchymal organs with hypothetical scenarios suggesting how ACKR4 scavenging its cognate chemokines might affect the pathophysiology of these organs. Here we investigated the expression of ACKR4 in murine kidney and assessed its contribution to nephrotoxic serum nephritis (NTSN), an experimental murine model of immune complex glomerulonephritis.

Methods

Expression of renal ACKR4 was evaluated in healthy ACKR4-eGFP reporter mice as well as after the induction of NTSN. To investigate the contribution of ACKR4 to the NTSN the ACKR4-deficient mice and WT controls were subjected to an anti-basal membrane immunization protocol and the parameters of immunopathogenesis and the ensuing kidney disease were evaluated at 7 and 14 days after the immunization.

Results

We found that ACKR4 is expressed in the kidney exclusively in the glomeruli by a discrete subset of parietal cells localising adjacently to the vascular glomerular pole. In mice with NTSN the expression of ACKR4 was diminished and ACKR4+ cells were even missing from some glomeruli, especially in those corresponding with the increased abundance of alpha-SMA, a marker of renal fibrosis. The ACKR4-deficient mice showed a delayed antibody response following immunisation. However, despite this, their NTSN parameters, including albuminuria, PAS-score and crescent formation were significantly increased as compared to the WT controls.

Conclusion

ACKR4 is expressed in the kidney by a small subpopulation of glomerular cells and it is decreased during NTSN. Reduced antibody titters following immunisation of ACKR4-deficient mice are in line with its contribution to the effective cell migratory steps within the immune organs. Conversely, the more severe appearance of NTSN in these mice, suggests that ACKR4 in the kidney plays a regulatory role limiting the development of this experimental disease.