ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: TH-PO1058

Non-Canonical Expression of CCR2 on Renal Progenitor Cells and Activated Parietal Epithelial Cells: Key to Therapeutic Effect of CCR2 Inhibition in CKD?

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Zhao, Bin N., ChemoCentryx, Mt View, California, United States
  • Miao, Zhenhua, ChemoCentryx, Mt View, California, United States
  • Campbell, James J., ChemoCentryx, Mt View, California, United States
  • Ertl, Linda, ChemoCentryx, Mt View, California, United States
  • Zang, Xiaoping, ChemoCentryx, Mt View, California, United States
  • Wang, Yu, ChemoCentryx, Mt View, California, United States
  • Li, Chris, ChemoCentryx, Mt View, California, United States
  • Singh, Rajinder, ChemoCentryx, Mt View, California, United States
  • Charo, Israel, ChemoCentryx, Mt View, California, United States
  • Schall, Thomas J., ChemoCentryx, Mt View, California, United States
Background

Rapid benefits to proteinuria and renal structure are seen with inhibition of CCR2 in models of diabetic nephropathy (DN) and focal segmental glomerulosclerosis (FSGS), and in a human DN trial. However, the mechanism of CCR2 inhibition in renal protection is unclear. Known expression of CCR2 on monocytes does not adequately explain the rapid pharmacologic benefits observed. We used a variety of methods to characterize CCR2 expression on renal progenitor cells (RPCs, CD133+CD24+) in Bowman's capsule, and on activated parietal epithelial cells (PECs, CD133+CD24+CD44+), which play a role in glomerulosclerosis.

Methods

One copy of CCR2 was replaced by red fluorescent protein (RFP) under the control of the mouse CCR2 promoter. CCR2-RFP mouse glomeruli were obtained by a non-enzymatic disruption of kidneys, sieving and low speed centrifugation and analyzed by flow cytometry for CCR2 expression. CCR2 in FSGS was modeled by Adriamycin (ADR) induced kidney injury.

Results

CCR2-RFP positive cells were detected in CD45 positive and CD45 negative renal cell populations. The majority of renal CD45- RFP+ cells were CD133 positive but CD24 negative, and are yet largely uncharacterized. However CD133+CD24+ RPC’s, while unchanged in absolute number before and after ADR challenge, showed a dramatic increase (20-40 fold) in the proportion that were CCR2-RFP+ after ADR injury. Furthermore, after ADR challenge, the expression of CD44 (a marker for activated PECs) was increased in the CD133+CD24+ population. Immunofluorescence confirmed an RFP signal in the glomeruli and Bowman's capsule.

Conclusion

This is the first report of the presence of CCR2 on non-hematopoietic renal parenchymal cells. The non-canonical CCR2+ cells are positive for CD133, CD24, and CD44 consistent with their being renal progenitor cells and activated PECs. These populations are markedly upregulated during kidney injury. These cells may be the targets of the CCR2 inhibitors that have been shown to be efficacious in murine models of CKD, as well as in human DN patients. CCR2 antagonism represents a novel approach for the treatment of CKD, including FSGS, and these studies are an important step in understanding the mechanism of their therapeutic benefit.