Academic Journal
Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy
| العنوان: | Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy |
|---|---|
| المؤلفون: | Boels, M.G., Koudijs, A., Avramut, M.C., Sol, W., Wang, G., Oeveren-Rietdijk, A.M. van, Zonneveld, A.J. van, Boer, H.C. de, Vlag, J. van der, Kooten, C. van, Eulberg, D., Berg, B.M., DHT, I.J., Rabelink, T.J. |
| المصدر: | American Journal of Pathology, 187, 11, pp. 2430-2440 |
| سنة النشر: | 2017 |
| المجموعة: | Radboud University: DSpace |
| مصطلحات موضوعية: | Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences |
| الوصف: | Contains fulltext : 182393.pdf (Publisher’s version ) (Open Access) ; 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| Relation: | https://repository.ubn.ru.nl//bitstream/handle/2066/182393/182393.pdf; http://hdl.handle.net/2066/182393; https://doi.org/10.1016/j.ajpath.2017.07.020 |
| DOI: | 10.1016/j.ajpath.2017.07.020 |
| الاتاحة: | http://hdl.handle.net/2066/182393 https://repository.ubn.ru.nl//bitstream/handle/2066/182393/182393.pdf https://doi.org/10.1016/j.ajpath.2017.07.020 |
| رقم الانضمام: | edsbas.FEA3A68C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ajpath.2017.07.020 |
|---|