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Abstract: PO1738

Angiotensin Converting Enzyme-Overexpressing Neutrophils Suppress Glomerular Injury in Crescentic Glomerulonephritis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Tatsumoto, Narihito, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Saito, Suguru, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Nishi, Hiroshi, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
  • Bernstein, Kenneth E., Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Yamashita, Michifumi, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States
Background

Angiotensin Converting Enzyme (ACE) is well known as the responsible enzyme to regulate blood pressure by producing angiotensin II in renin-angiotensin system, while recent studies have revealed that ACE has a novel function in immune cells. We previously found that ACE overexpressed myeloid lineage cells promoted an inflammatory response resulting in increasing resistance to bacterial infection and tumor growth. These results prompt us to investigate the effect of overexpressed ACE in myeloid lineage cells on immune complex (IC)-mediated crescentic glomerulonephritis (GN).

Methods

We induced the nephrotoxic serum nephritis (NTN) in C57Bl/6 (WT), and NeuACE mice that overexpressing ACE in neutrophils. In addition, IC uptake and IC-mediated responses were investigated in both WT and NeuACE neutrophils by ex vivo experiments.

Results

Seven days after induction of NTN, NeuACE mice showed less severe proteinuria, histological glomerular injury, and less number of macrophages infiltration into the glomeruli than those in WT mice. While production and serum level of autologous antibody titer were comparable, IC deposits in glomeruli were reduced in NeuACE mice compared to WT mice. In ex vivo experiments, IC uptaking was significantly promoted in NeuACE neutrophils as compared to WT cells. As an underlying mechanism of the promoted IC uptaking in neutrophils, we found that serum level of complement C3b and expression of complement receptor CR1/2 on neutrophils were significantly elevated in NeuACE mice. Furthermore, we confirmed that anti-CR1/2 blocking antibody abolished the uptaking of IC in neutrophils and the NeuACE serum enhanced IC uptake in both normal and ACE overexpressing neutrophils. These results suggest that ACE in neutrophils directly or indirectly pre-activate C3, and that both the elevated CR1/2 expression and the increased serum C3b play the pivotal role in IC uptake by neutrophils. Despite the increase in IC uptaking, neutrophils from NeuACE mice showed better cell survival after IC stimulation compared to those from WT mice.

Conclusion

Overexpressed ACE in neutrophils contributes to the effective elimination and suppression of IC deposits in glomeruli via C3b-CR1/2 axis, ameliorating glomerular injury in crescentic GN. These results indicate a novel immunological aspect of ACE in GN.

Funding

  • Other NIH Support