Kidney Week

Abstract: SA-PO316

The Atypical Chemokine Receptor 2 Limits Fibrotic Remodelling after Ischemia-Reperfusion Injury of the Kidney

Session Information

• Mechanisms Associated with Kidney Fibrosis - II
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Chronic Kidney Disease (Non-Dialysis)

• 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

• Lux, Moritz X, Ludwig-Maximilians-University Munich, Munich, Germany

Moritz X Lux,

• Bideak, Andrei, Ludwig-Maximilians-University Munich, Munich, Germany

Andrei Bideak,

• Blaut, Alexander, Ludwig-Maximilians-University Munich, Munich, Germany

Alexander Blaut,

• Eltrich, Nuru, Ludwig-Maximilians-University Munich, Munich, Germany

Nuru Eltrich,

• Vielhauer, Volker, Ludwig-Maximilians-University Munich, Munich, Germany

Volker Vielhauer,

Background

Acute kidney injury (AKI) is a risk factor for the development of chronic kidney disease (CKD). After ischemia-reperfusion-injury (IRI), a major aetiology of human AKI, resolution of renal inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of CKD. The atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor, which scavenges inflammatory CC-chemokines and reduces local leukocyte accumulation and inflammation.

Methods

Here, we hypothesized that ACKR2 limits leukocyte infiltration, inflammation and fibrotic tissue remodelling after renal IRI, thus preventing progression to CKD after AKI. We tested this hypothesis by subjecting wild-type (WT) and Ackr2-deficient mice to IRI induced by transient renal pedicle clamping. In addition, in vitro experiments were performed with tubulointerstitial tissue isolated form wild-type and Ackr2-/- mice.

Results

Compared to WT control Ackr2 deficiency lead to significantly increased CCL2 levels in TNF-stimulated tubulointerstitial tissue in vitro. In vivo, Ackr2 deficiency did not affect renal dysfunction and tubular injury in early IRI one day after bilateral or 5 days after unilateral pedicle clamping, although accumulation of mononuclear phagocytes increased in postischemic Ackr2-/- kidneys. Regarding long-term outcomes, postischemic Ackr2-/- kidneys displayed significantly more tubular injury 5 weeks after unilateral IRI, which was associated with persistent increases in mononuclear phagocyte and T cell infiltrates compared to WT. Moreover, Ackr2 deficiency resulted in more severe inflammation in postischemic kidneys, with increased expression of proinflammatory chemokines and M1 macrophage markers, and enhanced accumulation of Ly6C^high inflammatory macrophages. This was associated with aggravated renal fibrosis in Ackr2-/- kidneys 5 weeks after IRI, as revealed by increased expression of matrix molecules, renal accumulation of αSMA+ myofibroblasts and enhanced renal infiltration of bone marrow-derived fibrocytes.

Conclusion

These data suggest that the chemokine decoy receptor ACKR2 plays an important role in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic AKI, and thus prevents subsequent progression to CKD.

Funding

• Government Support - Non-U.S.