PMID- 28837800 OWN - NLM STAT- MEDLINE DCOM- 20171128 LR - 20171128 IS - 1525-2191 (Electronic) IS - 0002-9440 (Linking) VI - 187 IP - 11 DP - 2017 Nov TI - Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy. PG - 2430-2440 LID - S0002-9440(17)30006-8 [pii] LID - 10.1016/j.ajpath.2017.07.020 [doi] AB - 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. CI - Copyright (c) 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Boels, Margien G S AU - Boels MGS AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Koudijs, Angela AU - Koudijs A AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Avramut, M Cristina AU - Avramut MC AD - Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Sol, Wendy M P J AU - Sol WMPJ AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Wang, Gangqi AU - Wang G AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - van Oeveren-Rietdijk, Annemarie M AU - van Oeveren-Rietdijk AM AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - van Zonneveld, Anton Jan AU - van Zonneveld AJ AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - de Boer, Hetty C AU - de Boer HC AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - van der Vlag, Johan AU - van der Vlag J AD - Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands. FAU - van Kooten, Cees AU - van Kooten C AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Eulberg, Dirk AU - Eulberg D AD - NOXXON Pharma AG, Berlin, Germany. FAU - van den Berg, Bernard M AU - van den Berg BM AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - IJpelaar, Daphne H T AU - IJpelaar DHT AD - Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. FAU - Rabelink, Ton J AU - Rabelink TJ AD - 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. LA - eng PT - Journal Article DEP - 20170822 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Ccl2 protein, mouse) RN - 0 (Chemokine CCL2) SB - IM MH - Animals MH - Chemokine CCL2/*metabolism MH - Diabetes Mellitus, Experimental/metabolism MH - Diabetic Nephropathies/*metabolism/pathology MH - Glycocalyx/*metabolism MH - Kidney/pathology MH - Macrophages/*metabolism MH - Male MH - Mice, Knockout MH - Monocytes/metabolism MH - Podocytes/*metabolism EDAT- 2017/08/25 06:00 MHDA- 2017/11/29 06:00 CRDT- 2017/08/25 06:00 PHST- 2017/01/05 00:00 [received] PHST- 2017/06/26 00:00 [revised] PHST- 2017/07/05 00:00 [accepted] PHST- 2017/08/25 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2017/08/25 06:00 [entrez] AID - S0002-9440(17)30006-8 [pii] AID - 10.1016/j.ajpath.2017.07.020 [doi] PST - ppublish SO - Am J Pathol. 2017 Nov;187(11):2430-2440. doi: 10.1016/j.ajpath.2017.07.020. Epub 2017 Aug 22.