Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy.

Autor:	Boels MGS; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., Koudijs A; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., Avramut MC; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands., Sol WMPJ; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., Wang G; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., van Oeveren-Rietdijk AM; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., van Zonneveld AJ; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., de Boer HC; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., van der Vlag J; Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands., van Kooten C; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., Eulberg D; NOXXON Pharma AG, Berlin, Germany., van den Berg BM; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., IJpelaar DHT; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands., Rabelink TJ; Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: a.j.rabelink@lumc.nl.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2017 Nov; Vol. 187 (11), pp. 2430-2440. Date of Electronic Publication: 2017 Aug 22.
DOI:	10.1016/j.ajpath.2017.07.020
Abstrakt:	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. Because 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 of treatment of diabetic Apoe knockout mice with the mouse-specific NOX-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 Ly6C hi monocytes in the peripheral blood, without affecting overall number of kidney macrophages at the tissue level. However, the 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 IL-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mouse-specific NOX-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. (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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