Abstract: FR-PO959
Deficiency of the Atypical Chemokine Receptor 2 (ACKR2) Accelerates Progression of Nephrocalcinosis-Related CKD
Session Information
- Pathology and Lab Medicine: Basic
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1601 Pathology and Lab Medicine: Basic
Authors
- Blaut, Alexander, Ludwig-Maximilians-University Munich, Munich, Germany
- Eltrich, Nuru, Ludwig-Maximilians-University Munich, Munich, Germany
- Anders, Hans J., Ludwig-Maximilians-University Munich, Munich, Germany
- Mulay, Shrikant Ramesh, Ludwig-Maximilians-University Munich, Munich, Germany
- Vielhauer, Volker, Ludwig-Maximilians-University Munich, Munich, Germany
Background
Primary and secondary hyperoxaluria lead to deposition of calcium oxalate crystals in the kidney, i.e. nephrocalcinosis. Calcium oxalate-induced necroinflammation is an important mechanism of kidney injury in nephrocalcinosis. The atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor expressed in the tubulointerstitium, which scavenges inflammatory CC-chemokines and reduces renal inflammation in chronic kidney disease models. We therefore hypothesized that ACKR2 limits renal inflammation and fibrotic tissue remodeling in nephrocalcinosis-related chronic kidney disease and slows progression to end-stage renal failure.
Methods
Chronic oxalate nephropathy was induced in wild-type and Ackr2-deficient (Ackr2-/-) mice by feeding an oxalate-rich and calcium-depleted diet. Renal functional decline was monitored by measurement of glomerular filtration rates in weekly intervals until day 14. Renal injury, inflammation and fibrosis were assessed at day 14.
Results
Compared to wild-type, Ackr2-/- mice showed increased mortality following induction of oxalate nephropathy. Renal function declined more rapidly in Ackr2-/- mice, leading to end-stage renal failure until day 14. Tubular injury was worse in Ackr2-/- mice. Tubulointerstitial infiltrates of granulocytes and mononuclear phagocytes, but not T cells increased in Ackr2-/- kidneys. Moreover, Ackr2 deficiency aggravated renal inflammation, with increased expression of the inflammatory chemokine CCL2 and enhanced accumulation of CCR2+ inflammatory macrophages. Renal expression of annexin II and CD44, which mediate adhesion of calcium oxalate crystals to tubular epithelial cells, was increased in Ackr2-/- mice. This may contribute to more extensive crystal deposition present in Ackr2-/- kidneys despite comparable calciuria and oxalate levels to wild-type. More severe renal injury and inflammation in Ackr2-/- mice was paralleled by aggravated renal fibrosis, as revealed by increased expression of extracellular matrix molecules, renal accumulation of myofibroblasts and enhanced infiltration of bone marrow-derived fibrocytes.
Conclusion
This data suggest that ACKR2 limits renal inflammation, calcium oxalate deposition, tubular injury and renal fibrosis in nephrocalcinosis, and thus slows progression to end-stage kidney disease.
Funding
- Government Support - Non-U.S.