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Abstract: FR-PO1058

Deficiency for the Chemokine Receptor CCR2 Protects from Glomerular Injury and Interstitial Fibrosis in Adriamycin-Induced Glomerulosclerosis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Wilkening, Anja, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
  • Eltrich, Nuru, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
  • Luckow, Bruno, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
  • Vielhauer, Volker, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
Background

Glomerulosclerosis and tubulointerstitial fibrosis are hallmarks of chronic kidney injury leading to end-stage renal disease. Inflammatory mechanisms contribute to glomerular and interstitial scaring including chemokine-mediated recruitment of leukocytes. In particular, accumulation of chemokine receptor CCR2 expressing macrophages promotes renal injury and fibrotic remodeling in diseases like glomerulonephritis and diabetic nephropathy. However, whether CCR2 plays a functional role in the initiation and progression of primary glomerulosclerosis induced by podocyte injury remains unclear.

Methods

To explore potential pro-inflammatory and pro-fibrotic functions of CCR2 in focal segmental glomerulosclerosis (FSGS) we analyzed adriamycin-induced nephropathy, a murine model of FSGS, in BALB/c wild-type and Ccr2-deficient mice.

Results

In adriamycin-induced FSGS progressive glomerular scaring and reduced glomerular nephrin expression was paralleled by induced glomerular expression of the CCR2 chemokine ligand CCL2. In comparison to wild-type, Ccr2-deficient mice with adriamycin nephropathy showed reduced albuminuria and preserved renal function. Whereas the extent of glomerular podocyte and endothelial cell injury was similar, glomerular sclerosis and glomerular macrophage infiltration were reduced in Ccr2-deficient mice. Moreover, Ccr2 deficiency decreased tubular damage, interstitial leukocyte infiltration, renal inflammation and renal expression of extracellular matrix molecules. Consistently, tubulointerstitial fibrosis, accumulation of αSMA-positive myofibroblasts and renal fibroctyes were reduced in Ccr2-deficient kidneys.

Conclusion

Our data indicate that the chemokine receptor CCR2 contributes to glomerular scaring and interstitial fibrosis in FSGS by facilitating glomerular and tubulointerstitial infiltration of macrophages, renal inflammation, and renal accumulation of fibrocytes. Thus, CCR2 is an important mediator of glomerular injury and progression of FSGS. CCR2 targeting therapies may represent a novel approach for its treatment.

Funding

  • Government Support - Non-U.S.