CCR2 antagonism leads to marked reduction in proteinuria and glomerular injury in murine models of focal segmental glomerulosclerosis (FSGS)

PLoS One. 2018 Mar 21;13(3):e0192405. doi: 10.1371/journal.pone.0192405. eCollection 2018.

Abstract

Focal segmental glomerulosclerosis (FSGS) comprises a group of uncommon disorders that present with marked proteinuria, nephrotic syndrome, progressive renal failure and characteristic glomerular lesions on histopathology. The current standard of care for patients with FSGS include immunosuppressive drugs such as glucocorticoids followed by calcineurin inhibitors, if needed for intolerance or inadequate response to glucocorticoids. Renin-angiotensin-aldosterone (RAAS) blockers are also used to control proteinuria, an important signature of FSGS. Existing treatments, however, achieved only limited success. Despite best care, treatment failure is common and FSGS is causal in a significant proportion of end stage renal disease. Thus, an unmet need exists for novel disease modifying treatments for FSGS. We employed two widely-used murine models of FSGS to test the hypothesis that systemic inhibition of chemokine receptor CCR2 would have therapeutic benefit. Here we report that administration CCX872, a potent and selective small molecule antagonist of CCR2, achieved rapid and sustained attenuation of renal damage as determined by urine albumin excretion and improved histopathological outcome. Therapeutic benefit was present when CCX872 was used as a single therapy, and moreover, the combination of CCX872 and RAAS blockade was statistically more effective than RAAS blockade alone. In addition, the combination of CCR2 and RAAS blockade was equally as effective as endothelin receptor inhibition. We conclude that specific inhibition of CCR2 is effective in the Adriamycin-induced and 5/6 nephrectomy murine models of FSGS, and thus holds promise as a mechanistically distinct therapeutic addition to the treatment of human FSGS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria* / drug therapy
  • Albuminuria* / pathology
  • Albuminuria* / urine
  • Animals
  • Cell Line
  • Disease Models, Animal
  • Glomerulosclerosis, Focal Segmental* / drug therapy
  • Glomerulosclerosis, Focal Segmental* / pathology
  • Glomerulosclerosis, Focal Segmental* / urine
  • Humans
  • Kidney Glomerulus* / injuries
  • Kidney Glomerulus* / metabolism
  • Kidney Glomerulus* / pathology
  • Mice
  • Mice, Inbred BALB C
  • Receptors, CCR2 / antagonists & inhibitors*
  • Receptors, CCR2 / metabolism
  • Renin-Angiotensin System / drug effects*

Substances

  • Ccr2 protein, mouse
  • Receptors, CCR2

Grants and funding

This study was funded by ChemoCentryx, who provided support in the form of salaries for all authors but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.