G TESCH1,2, N PULLEN3, D NIKOLIC-PATERSON1,2
1Monash Health, Australia, 2Monash University Centre for Inflammatory Diseases, Clayton, Australia, 3Pfizer Worldwide Research & Development, Cambridge, USA
Aim: To evaluate intervention with a CCR2 antagonist (CCR2A) in a model of progressive diabetic glomerulosclerosis and determine whether a CCR2A provides added benefit over conventional treatment with an angiotensin converting enzyme inhibitor (ACEi).
Background: Blockade of chemokine CC motif receptor 2 (CCR2) inhibits kidney macrophage accumulation and suppresses early glomerular damage in diabetic animals. CCR2As are in clinical trials for diabetic nephropathy prompting investigation into whether they provide added benefit over ACEi.
Methods: Diabetes was induced in hypertensive endothelial nitric oxide synthase (Nos3) deficient mice by streptozotocin (STZ). Groups of diabetic Nos3-/- mice received a CCR2A (PF-04634817) as an early intervention (2-15 weeks after STZ). The late intervention (weeks 8-15 after STZ) involved PF-04634817 alone, ACEi (captopril) alone, or combined ACEi + CCR2A.
Results: Early intervention with CCR2A inhibited kidney inflammation and glomerulosclerosis, albuminuria, podocyte loss and renal function impairment, but not hypertension. Late intervention with CCR2A also inhibited kidney inflammation, glomerulosclerosis, renal dysfunction but did not affect albuminuria. ACEi alone suppressed hypertension and albuminuria, partially reduced podocyte loss and glomerulosclerosis, but did not affect renal dysfunction. Compared to ACEi alone, combined intervention with ACEi + CCR2A provided better protection against kidney damage (inflammation, glomerulosclerosis, renal function impairment), but not albuminuria.
Conclusion: Combining CCR2A and ACEi provides broader and superior renal protection than ACEi alone in a model of established diabetic glomerulosclerosis with hypertension.
Greg Tesch is head of diabetes research in the Nephrology Department at Monash Health. His work is primarily focused on understanding the inflammatory mechanisms which promote diabetic nephropathy and developing novel anti-inflammatory treatments for diabetic nephropathy and other chronic kidney diseases.