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.
Highlights
To determine if chemokine receptor 2 (CCR2) plays a key role in Focal segmental glomerulosclerosis (FSGS) we examined the ability of CCX872 to block radio-labeled CCR2 ligand, mJE (CCL2) binding in the WEHI-274 murine monocyte cell line that endogenously expresses CCR2 [17, 18]
These results indicate that CCR2 inhibition and endothelin A/angiotensin II receptors dual antagonist inhibition is effective when combined with RAAS blockade in this model of FSGS
FSGS is a progressive renal disease of both children and adults that rapidly progresses to endstage renal failure when accompanied by high proteinuria
Summary
Evidence for a direct causative role comes from [9], who reported that a well-characterized polymorphism in MCP-1 (MCP-1 2518 A/G) causes increased protein expression This increased MCP-1 expression is associated with greater risk of renal failure in both FSGS and IgA nephropathy patients. Podocytes, which are key players in pathologies involving proteinuria, directly express CCR2 and cultured human podocytes respond to MCP-1 in migration and cell-proliferation assays [10, 11]. Diabetic nephropathy, another disease characterized by progressive renal failure, presents with significant proteinuria and loss of podocytes [12,13,14]. We report that a CCR2 selective small molecule antagonist markedly reduced proteinuria and improved renal function in both of these widely used murine FSGS models, both as a single agent and when given in combination with RAAS and/or endothelin receptor antagonists
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