Abstract: SA-PO368
Expression of Chemokine Receptor 2 (CCR2) on Renal Podocyte Progenitor Stem Cells
Session Information
- Glomerular Diseases: Immunology and Inflammation - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Zhao, Bin N., Chemocentryx Inc., Mountain View, California, United States
- Miao, Zhenhua, ChemoCentryx, Mt View, California, United States
- Ertl, Linda, ChemoCentryx, Mt View, California, United States
- Zang, Xiaoping, ChemoCentryx, Inc., Mountain View, California, United States
- Charo, Israel, ChemoCentryx, Mt View, California, United States
- Schall, Thomas J., ChemoCentryx, Mt View, California, United States
- Singh, Rajinder, ChemoCentryx, Mt View, California, United States
Background
Several lines of evidence support a role for chemokine receptor 2 (CCR2) through interaction with its ligand CCL2 in the pathogenesis of kidney diseases. We have shown recently that inhibition of CCR2 by small molecule inhibitors markedly reduce proteinuria, improve renal function and preserve or restore podocyte density in murine models of Focal Segmental Glomerulosclerosis (FSGS). To understand the mechanism of this protection, we have examined the expression of CCR2 on human and murine kidneys.
Methods
CCR2 expression on the kidneys was assessed by immunohitochemistry (IHC) on formalin fixed, paraffin-embedded human and mouse kidney sections, and by flow cytometry with freshly isolated murine renal cells.
Results
IHC with a human CCR2 antibody revealed CCR2 expression on glomerular cells in human CCR2 knock-in, but not CCR2 knockout mouse kidneys. Flow cytometry of freshly isolated murine kidney cells confirmed CCR2 expression on CD45 negative-cells, indicating that the positive IHC signal was not due to mature blood cells. CD133 and CD24 are cell surface markers of a heterogeneous population of renal progenitor cells, and approximately 5% of these cells also express the podocyte marker podocalyxin (PDX), marking them as podocyte precursors. By flow cytometry we found that ~8% of the murine renal CD133+CD24+ PDX+ cells, were also positive for CCR2, indicating that CCR2 was present on a subset of cells destined to become mature podocytes. Finally we used IHC to examine CCR2 expression on human renal biopsies of FSGS patients and non FSGS patients and found out that increased staining for CCR2 in the FSGS kidneys in the glomerulus and Bowman’s capsule areas. These data provide clear evidence that CCR2, the target of the small molecule that we have shown reduces proteinuria and improves renal function in murine models of FSGS is present on non-hematopoietic cells in the kidney.
Conclusion
This is the first demonstration of the presence of CCR2 on renal progenitor cells that are destined to become podocytes, and reveals a potential new role for this chemokine receptor whose function as been heretofore mainly connected to monocyte/macrophage biology. Taken together, these data provide the foundation for a mechanistic understanding of the therapeutic benefit of CCR2 antagonists in FSGS, and possibly other renal diseases.
Funding
- Clinical Revenue Support