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-PO1057

CCR2 Inhibition Improves Glomerular Ultrastructure In Vivo in Models of Focal Segmental Glomerulosclerosis (FSGS)

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Miao, Zhenhua, ChemoCentryx, Inc., Mountain View, California, United States
  • Ertl, Linda, ChemoCentryx, Inc., Mountain View, California, United States
  • Newland, Dale, ChemoCentryx, Inc., Mountain View, California, United States
  • Zang, Xiaoping, ChemoCentryx, Inc., Mountain View, California, United States
  • Zhao, Bin N., ChemoCentryx, Inc., Mountain View, California, United States
  • Wang, Yu, ChemoCentryx, Inc., Mountain View, California, United States
  • Yau, Simon Kwok-Pan, ChemoCentryx, Inc., Mountain View, California, United States
  • Liu, Shirley, ChemoCentryx, Inc., Mountain View, California, United States
  • Dang, Ton Hy, ChemoCentryx, Inc., Mountain View, California, United States
  • Zhang, Penglie, ChemoCentryx, Inc., Mountain View, California, United States
  • Campbell, James J., ChemoCentryx, Inc., Mountain View, California, United States
  • Charo, Israel, ChemoCentryx, Inc., Mountain View, California, United States
  • Singh, Rajinder, ChemoCentryx, Inc., Mountain View, California, United States
  • Schall, Thomas J., ChemoCentryx, Inc., Mountain View, California, United States
Background

FSGS is a histologic diagnosis resulting from glomerular injury primarily affecting podocytes, and characterized by the presence of focal and segmental scarring in the glomeruli. Treatment failure is common with current standard of care, and FSGS is causal in at least 4% of patients with ESRD. Several lines of evidence support roles for CCR2 in the pathogenesis of CKD, including FSGS. We have recently shown that a CCR2 antagonist improved renal structure and reduced proteinuria in the murine models of FSGS. To further understand the mechanism by which CCR2 antagonism affords protection in FSGS, we have used EM to examine the effects of CCR2 antagonist on podocyte integrity.

Methods

The 5/6 nephrectomy model of murine FSGS was used to investigate the efficacy of CCR2 antagonist. Kidney injury was assessed by urinary albumin excretion rate (UAER), urine albumin creatinine ratio (UACR), histopathology and EM. Both transmission EM (TEM) and scanning EM (SEM) were performed on kidney samples.

Results

In 5/6 nephrectomized mice, UACR was rapidly and significantly reduced after treatment with CCR2 antagonist (42% and 77% reduction comparing to vehicle treated by week 1 and 2; p=0.04 and 0.025, respectively). The number of glomeruli with sclerosis was reduced by 54% based on analysis of 50-75 glomeruli per kidney. Podocyte integrity was also improved with CCR2 inhibition. Specifically, analysis by both SEM and TEM revealed that podocyte foot process (FP) effacement and slit diaphragm (SD) disruption were improved by CCR2 antagonism, as were the characteristically thickened and denuded GBM. After two weeks of treatment with CCR2 antagonist, FP number was significantly increased with respect to vehicle treated mice (2.10/um GBM vs 1.53/um GBM, p < 0.0001).

Conclusion

Treatment with CCR2 antagonist provides rapid renal protection in the murine model of FSGS, as measured by improved proteinuria and renal structure. Furthermore, CCR2 blockade protected podocyte integrity, as measured by both SEM and TEM. These results provide further evidence that specific inhibition of CCR2 has therapeutic potential in the treatment of FSGS. CCR2 antagonism thus represents a novel and mechanistically distinct approach for the treatment of FSGS.