SPLEEN TYROSINE KINASE DELETION IN MYELOID CELLS REDUCES MACROPHAGE INFILTRATION IN ARISTOLOCHIC ACID NEPHROPATHY IN MICE

X CHIA 1,3 E OZOLS 1,2,3, D NIKOLIC-PATERSON 1,2,3, G TESCH 1,2,3

1Department of Nephrology, Monash Health , Melbourne, Australia, 2Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Melbourne, Australia, 3Monash University, Melbourne, Australia

Aim: To investigate the role of spleen tyrosine kinase (SYK) in myeloid cell recruitment and activation in aristolochic acid nephropathy (AAN).

Background: AAN causes acute kidney injury (AKI) in mice with associated inflammatory cell infiltration. SYK blockade has been found to reduce macrophage and neutrophil infiltration in several models of AKI, including AKI induced by ischaemia-reperfusion injury, however its role in AAN has not been investigated.

Methods: AAN was induced in Sykf/f Csf1rCre mice with selective Syk gene knockout in myeloid cells, and control Sykf/f mice. Comparison was made with no disease controls. Periodic acid-Schiff stain and immunohistochemistry staining was performed to assess for tubular damage and leucocyte infiltration. RNA expression of markers of injury and inflammation was examined by RT-PCR.

Results: Compared to no disease, control Sykf/f mice at day 3 of AAN had a 2.95-fold increase in serum creatinine (p<0.01), a 1.44-fold increase in serum urea (p<0.01), substantial tubular injury (kidney KIM1 mRNA ↑229-fold, p<0.01, and tubular histological damage) and increased infiltration of macrophages (F4/80+ cells ↑1.45-fold, p=0.04; kidney CD68 mRNA ↑12-fold, p<0.01) and neutrophils (Ly6G+ cells ↑3.46-fold, p<0.01). In comparison to control Sykf/f mice, Sykf/f Csf1rCre mice at day 3 of AAN had reduced macrophage infiltration (F4/80+ cells ↓30%, p=0.03; kidney CD68 mRNA ↓25%, p=0.02) . However, there was no significant effect on neutrophil infiltration, serum creatinine, serum urea, histological damage or other markers of injury or inflammation.

Conclusion: During early injury in AAN, kidney recruitment of macrophages, but not neutrophils, depends upon SYK. Further study is required to determine how neutrophil recruitment differs in AAN compared to other AKI models where SYK is known to play a role.


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