3 years ago

Systemic monocyte chemotactic protein-1 inhibition modifies renal macrophages and restores glomerular endothelial glycocalyx and barrier function in diabetic nephropathy

Inhibition of monocyte chemotactic protein-1 (MCP)-1 with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Since the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx degrading enzyme heparanase. Four weeks treatment of diabetic Apoe KO mice with the mouse specific mNOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6Chi monocytes in the peripheral blood without affecting overall number of kidney macrophages at the tissue level. However, CD206+/Mac3+ cell ratio as an index of presence of anti-inflammatory macrophages increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of interleukin-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mNOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy.

Publisher URL: www.sciencedirect.com/science

DOI: S0002944017300068

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