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. 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 Ly6Chi 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. 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 Ly6Chi 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. Diabetic nephropathy is the major cause of end-stage renal disease. Although optimal blood pressure treatment using drugs that interfere with the renin-angiotensin system has been shown to slow progression of diabetic nephropathy, many patients still progress to end-stage renal disease.1US Renal Data System Annual Data Report. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Edited by National Institutes of Health. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases, 2016. Available at https://www.usrds.org/adr.aspxGoogle Scholar In recent years, new strategies to slow the progression of chronic kidney disease in patients with diabetic nephropathy focused on inhibition of inflammation.2Heerspink H.J. De Zeeuw D. Novel anti-inflammatory drugs for the treatment of diabetic kidney disease.Diabetologia. 2016; 59: 1621-1623Crossref PubMed Scopus (16) Google Scholar One such strategy constitutes inhibition of monocyte chemotactic protein-1 (MCP-1) to prevent binding to its cognate receptor CCR2. MCP-1 is considered to be involved in recruitment of monocytes and migration of monocytes and macrophages.3Van Coillie E. Van Damme J. Opdenakker G. The MCP/eotaxin subfamily of CC chemokines.Cytokine Growth Factor Rev. 1999; 10: 61-86Crossref PubMed Scopus (266) Google Scholar, 4Haller H. Bertram A. Nadrowitz F. Menne J. Monocyte chemoattractant protein-1 and the kidney.Curr Opin Nephrol Hypertens. 2016; 25: 42-49Crossref PubMed Scopus (113) Google Scholar, 5Biswas S.K. Sodhi A. Paul S. Regulation of nitric oxide production by murine peritoneal macrophages treated in vitro with chemokine monocyte chemoattractant protein 1.Nitric Oxide. 2001; 5: 566-579Crossref PubMed Scopus (44) Google Scholar, 6Biswas S.K. Sodhi A. In vitro activation of murine peritoneal macrophages by monocyte chemoattractant protein-1: upregulation of CD11b, production of proinflammatory cytokines, and the signal transduction pathway.J Interferon Cytokine Res. 2002; 22: 527-538Crossref PubMed Scopus (55) Google Scholar In patients with diabetic nephropathy, the increased presence of MCP-1 in renal tissue and elevated levels in urine suggest that macrophages play a pathogenic role in the development of proteinuria, glomerular damage, and the progression of renal disease in humans.7Tashiro K. Koyanagi I. Saitoh A. Shimizu A. Shike T. Ishiguro C. Koizumi M. Funabiki K. Horikoshi S. Shirato I. Tomino Y. Urinary levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and renal injuries in patients with type 2 diabetic nephropathy.J Clin Lab Anal. 2002; 16: 1-4Crossref PubMed Scopus (111) Google Scholar Indeed, Nguyen et al8Nguyen D. Ping F. Mu W. Hill P. Atkins R.C. Chadban S.J. Macrophage accumulation in human progressive diabetic nephropathy.Nephrology. 2006; 11: 226-231Crossref PubMed Scopus (212) Google Scholar showed that macrophages are already present in glomeruli in early diabetic nephropathy, whereas the number of interstitial macrophages correlates with progression of renal insufficiency. Recently, we demonstrated similar findings in a large autopsy study showing that glomerular macrophages were already present in biopsy specimens with mild diabetic nephropathy, suggesting a role for macrophages in proteinuria and early diabetes–induced damage.9Klessens C.Q. Zandbergen M. Wolterbeek R. Bruijn J.A. Rabelink T.J. Bajema I.M. IJpelaar D.H.T. Macrophages in diabetic nephropathy in patients with type 2 diabetes.Nephrol Dial Transplant. 2017; 32: 1322-1329PubMed Google Scholar In experimental models of streptozotocin-induced diabetic nephropathy, macrophage recruitment to the glomeruli could be prevented by genetic deletion of MCP-1.10Chow F.Y. Nikolic-Paterson D.J. Ozols E. Atkins R.C. Rollin B.J. Tesch G.H. Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice.Kidney Int. 2006; 69: 73-80Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Similarly, pharmacological blockade of MCP-1 prevented glomerular macrophage recruitment and attenuated albuminuria in uninephrectomized db/db mice.11Ninichuk V. Clauss S. Kulkarni O. Schmid H. Segerer S. Radomska E. Eulberg D. Buchner K. Selve N. Klussmann S. Anders H.J. Late onset of Ccl2 blockade with the Spiegelmer mNOX-E36-3'PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice.Am J Pathol. 2008; 172: 628-637Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 12Darisipudi M.N. Kulkarni O.P. Sayyed S.G. Ryu M. Migliorini A. Sagrinati C. Parente E. Vater A. Eulberg D. Klussmann S. Romagnani P. Anders H.J. Dual blockade of the homeostatic chemokine CXCL12 and the proinflammatory chemokine CCL2 has additive protective effects on diabetic kidney disease.Am J Pathol. 2011; 179: 116-124Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar In addition, observations on alleviation of acute rejection through MCP-1 blockade point toward the potential of the MCP-1/CCR2 pathway to modulate inflammation. Clinically, the MCP-1/CCR2 axis has been targeted by receptor-specific antibodies and small molecules. For example, blockade of CCR2 with the small molecule CCX140-B in patients with diabetic nephropathy reduced albuminuria.13de Zeeuw D. Bekker P. Henkel E. Hasslacher C. Gouni-Berthold I. Mehling H. Potarca A. Tesar V. Heerspink H.J. Schall T.J. CCX140-B Diabetic Nephropathy Study GroupThe effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial.Lancet Diabetes Endocrinol. 2015; 3: 687-696Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar Recently, inhibition of MCP-1 with emapticap pegol (NOX-E36), a structured l-enantiomeric RNA (so-called Spiegelmer), decreased albuminuria in patients with diabetic nephropathy.14Menne J. Eulberg D. Beyer D. Baumann M. Saudek F. Valkusz Z. Wiecek A. Haller H. Emapticap Study GroupC-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria.Nephrol Dial Transplant. 2017; 32: 307-315Crossref PubMed Google Scholar The mechanism of the reduction in albuminuria by MCP-1 inhibition, however, is still not understood. The glomerular barrier for albumin filtration is an interplay between endothelial cells, podocytes, and the glomerular basement membrane. Fenestrated glomerular endothelial cells are covered with the glycocalyx, a gel-like polyanionic carbohydrate layer with embedded proteins.15Boels M.G. Avramut M.C. Koudijs A. Dane M.J. Lee D.H. van der J. van van E. H.J. van Rabelink T.J. reduces albuminuria by the glomerular endothelial glycocalyx barrier in diabetic 2016; PubMed Scopus Google Scholar, M. J. J.A. C. F. M. H. glycocalyx with in type 2006; PubMed Scopus Google Scholar of glycocalyx-degrading such as heparanase and has been in diabetic M.J. J. N. P. R. E. I. van der J. expression of heparanase in diabetic Int. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar The of is as an by endothelial cells and podocytes, is increased after activation by the enzyme cathepsin M. H. van Rabelink T.J. T. van der J. L is for the development of early experimental diabetic Int. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar L also be the by glomerular macrophages, cells for renal heparanase activation and loss of mechanism of of MCP-1 inhibition was in study in diabetic Apoe knockout mice and further in cell isolated macrophages of the renal tissue of Apoe mice were as M.G. Avramut M.C. Koudijs A. Dane M.J. Lee D.H. van der J. van van E. H.J. van Rabelink T.J. reduces albuminuria by the glomerular endothelial glycocalyx barrier in diabetic 2016; PubMed Scopus Google Scholar In in was for Apoe mice weeks after of mice were treated with of mouse-specific NOX-E36 Spiegelmer in a for is on with in A. M.N. M. S. A. S. M. Klussmann S. T. M. J. M. J. Spiegelmer inhibition of potential as an in J 2015; PubMed Scopus Google were the of and were weeks after treatment for were to after in diabetic to the and Apoe mice were with for were by the on and of the the was in with the were using a prevent and diabetic mice were treated blood levels were with to 2 of blood pressure was with the system in mice at the and of and at the of the using the system to treatment for Apoe urine was at study and after the treatment In a of urine was also weeks after of the treatment. were to after urine was levels were with Urinary levels were by the using and using a after were with an Urinary MCP-1 were with to the by the mice treatment were by and the with albumin and to Kidney were and of the kidney was in for to 2 by for and and of macrophages. The of the for was to of Diabetic using in Bethesda, to The was in for kidney were in for at binding was prevented by with in for heparanase expression was after with in with cell by for both in were with and embedded in L was by and was on as using was further on with antibodies heparan and van der and were after with in was further in kidney by with antibodies by for was as in Macrophages were using a S. a the J 11: PubMed Scopus Google a receptor by S. of by macrophage expression of for and and differentiation Google and a the The number of macrophages present was in a of glomeruli in in of to for endothelial glycocalyx was with as M.G. Avramut M.C. Koudijs A. Dane M.J. Lee D.H. van der J. van van E. H.J. van Rabelink T.J. reduces albuminuria by the glomerular endothelial glycocalyx barrier in diabetic 2016; PubMed Scopus Google Scholar In the kidney of mice was with albumin and in at 2 to blood, by 2 of in at 2 were with in at The kidney was with and in and on were embedded in and at for were further with and were at an of on a the with an of were with and using Avramut M.C. van of PubMed Scopus Google Scholar The large an of the in for The to the polyanionic glycocalyx, be the were and glycocalyx was in to in glomeruli The of of the with was using an in the For a of were at the of and for treatment were with albumin and to blood and in were small and with type and for at were through a cell and a cell to a cell The and strategy is in For of between the and kidney a index was as in the is as for T. J. for A. PubMed Scopus Google Scholar of cells was on an and were using blood, the was The renal cells were on a and macrophages were isolated and in a at a of in with and were at in a of cells were with for was for IL-10, and tumor necrosis factor levels with as as for cathepsin L to the Data are as in during treatment were using analysis of with analysis in that the are not in were using analysis of and with of expression between was using a was considered levels in Apoe mice after and were elevated during the weeks to the of treatment to to V. Clauss S. Kulkarni O. Schmid H. Segerer S. Radomska E. Eulberg D. Buchner K. Selve N. Klussmann S. Anders H.J. Late onset of Ccl2 blockade with the Spiegelmer mNOX-E36-3'PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice.Am J Pathol. 2008; 172: 628-637Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, A. M.N. M. S. A. S. M. Klussmann S. T. M. J. M. J. Spiegelmer inhibition of potential as an in J 2015; PubMed Scopus Google Scholar, J. M. F. V. D. C. K. Eulberg D. T. F. C. T. F. macrophages in progressive PubMed Scopus (191) Google Scholar treatment with Spiegelmer as a for weeks resulted in levels not not the blood levels for and levels during the weeks of In in Apoe mice blood levels during the experimental and the of the of the of mice was to mice both of were Apoe mice change in was at the of the was still with Apoe mice observations are of in blood we blood pressure and after treatment and at the of the in blood pressure were between diabetic and mice at and after the experimental at weeks of and at weeks of of diabetic Apoe mice for weeks with reduced the to in to treatment with Spiegelmer mice an of Because MCP-1 inhibition in diabetic patients a effect with to reduced J. Eulberg D. Beyer D. Baumann M. Saudek F. Valkusz Z. Wiecek A. Haller H. Emapticap Study GroupC-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria.Nephrol Dial Transplant. 2017; 32: 307-315Crossref PubMed Google Scholar we also albumin after a Four weeks after of mice still showed a toward a to diabetic mice treatment and the were in in to diabetic Apoe mice to podocyte injury, were in the number of expression of and on MCP-1 inhibition and not prevent interstitial injury, as by similar kidney injury levels not Urinary MCP-1 were the of in Apoe mice as as diabetic Apoe is in of the that observations be by at the tissue level. However, increased MCP-1 were in the mice treated with after weeks of treatment whereas levels were weeks after of treatment findings are in with observations by et M.N. Kulkarni O.P. Sayyed S.G. Ryu M. Migliorini A. Sagrinati C. Parente E. Vater A. Eulberg D. Klussmann S. Romagnani P. Anders H.J. Dual blockade of the homeostatic chemokine CXCL12 and the proinflammatory chemokine CCL2 has additive protective effects on diabetic kidney disease.Am J Pathol. 2011; 179: 116-124Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar demonstrated that an with its is and is in the In MCP-1 the of the we the effect of treatment on the glomerular endothelial glycocalyx coverage, the layer in the glomerular filtration was and by binding to the glomerular endothelial glycocalyx Renal resulted in binding to the endothelial cell also the The as an that showed on the of the in the glomerular basement were for Diabetes resulted in endothelial at weeks of with Apoe mice with increased glomerular glycocalyx to a to glomeruli the endothelial glycocalyx has a its on treatment weeks after toward a effect of the treatment. in diabetic mice was reduced with Apoe whereas in mice still with diabetic mice The in glomerular endothelial glycocalyx were further with to glycocalyx heparan and were using and heparan both and Diabetes reduced glomerular expression to whereas in expression was to mice and levels were reduced in diabetic in were to mice and Four weeks after of was still a effect with to both the diabetes effect on heparan and the by expression was by diabetes by treatment at and The glycocalyx of and of heparan are the the mechanism of glycocalyx on we at the expression of the heparan enzyme heparanase. Diabetic mice show increased glomerular heparanase protein expression with Apoe mice and of diabetic mice with reduced glomerular heparanase protein expression to effect present weeks after treatment with is by cathepsin M. H. van Rabelink T.J. T. van der J. L is for the development of early experimental diabetic Int. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, G. R. T. C. J.A. I. L is for and activation of through of a 2008; PubMed Scopus Google Scholar We showed by that the macrophage with cathepsin M.G. Avramut M.C. Koudijs A. Dane M.J. Lee D.H. van der J. van van E. H.J. van Rabelink T.J. reduces albuminuria by the glomerular endothelial glycocalyx barrier in diabetic 2016; PubMed Scopus Google Scholar with the elevated heparanase increased glomerular cathepsin L protein expression was in diabetic Apoe mice in and after treatment with a reduced cathepsin L expression was reduced and However, weeks after of cathepsin L expression in the was not diabetic mice cells, such as monocytes and macrophages, cathepsin Although the number of peripheral blood monocytes not change on treatment with analysis and not a of CCR2 was on the Ly6Chi of monocytes Ly6Chi in on MCP-1/CCR2 recruitment to C. Monocyte recruitment during and 2011; 11: PubMed Scopus Google Scholar In the reduced CCR2 expression on cells with increased chemokine receptor receptor chemokine receptor expression not F. S. monocytes of with Full Text Full Text PDF PubMed Scopus Google Scholar that the number of macrophages in the and glomerular was increased in diabetic mice with change in number of macrophages was on MCP-1 inhibition on and analysis of CD206+/Mac3+ cells showed that in the of CD206+/Mac3+ macrophages the glomeruli analysis to macrophages in kidney in change of macrophage number at and at and as as CCR2 expression of monocytes The phenotype of renal macrophages was further in renal and macrophages diabetic mice treated with Spiegelmer and were with to Macrophages diabetic mice with increased production and release of to was to macrophages of mice The production of as an with both proinflammatory and anti-inflammatory P. M. R. M. O. T. M. IL-10, and in the of the and the Int. Full Text Full Text PDF PubMed Scopus Google Scholar not between However, release of the proinflammatory was decreased on treatment with the reduction in and the overall anti-inflammatory expression of renal macrophages after treatment with a in cathepsin L was reduced by to In addition, a similar effect on cathepsin L by murine macrophages after MCP-1 and the of macrophages to cathepsin In the present we show that MCP-1 inhibition in diabetic nephropathy reduces albuminuria in with of glomerular endothelial glycocalyx effect was in the of and in the presence of podocyte injury, the of the glomerular endothelial glycocalyx for its barrier function. MCP-1 inhibition was also by a reduction in glomerular cathepsin L and heparanase expression in as as a toward anti-inflammatory renal macrophages, as we could show after One of polarization of macrophage function by MCP-1 inhibition is a decreased to cathepsin In a diabetic the glycocalyx is in a M.J. J. N. P. R. E. I. van der J. expression of heparanase in diabetic Int. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, R. N. E. van der J. R. A. M. of inflammatory in of diabetic PubMed Scopus Google Scholar In was by in heparan as as reduction of whereas not In heparanase is as by podocytes, endothelial cells, and T.J. Zeeuw D. The albuminuria with renal and 2015; 11: PubMed Scopus (111) Google Scholar of after the early and through cathepsin A. F. V. S. Y. S. I. N. and activation of heparanase in PubMed Scopus Google Scholar L its heparan G. R. T. C. J.A. I. L is for and activation of through of a 2008; PubMed Scopus Google Scholar after heparanase F. Y. D. P. of heparanase in endothelial 32: PubMed Scopus Google Scholar However, macrophages also cathepsin L during thus the activation of in the Z. C. and PubMed Scopus Google Scholar, T.J. van M. G. M. van der J. in cell and the development of kidney 2017; PubMed Scopus Google Scholar be further by in the M. S. N. and binding in both human type diabetic and and with inflammatory cells in PubMed Scopus Google Scholar as as by heparanase that macrophages by receptor R. N. E. van der J. R. A. M. of inflammatory in of diabetic PubMed Scopus Google Scholar in CCR2 expression proinflammatory F. S. monocytes of with Full Text Full Text PDF PubMed Scopus Google Scholar reduces CCR2 expression in peripheral monocytes in as was in the J. Eulberg D. Beyer D. Baumann M. Saudek F. Valkusz Z. Wiecek A. Haller H. Emapticap Study GroupC-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria.Nephrol Dial Transplant. 2017; 32: 307-315Crossref PubMed Google Scholar suggesting inflammatory potential and toward MCP-1 in H. Bertram A. Nadrowitz F. Menne J. Monocyte chemoattractant protein-1 and the kidney.Curr Opin Nephrol Hypertens. 2016; 25: 42-49Crossref PubMed Scopus (113) Google Scholar tissue levels in the and kidney of CCR2-expressing monocytes were not reduced. we that the of kidney Although was in number of renal macrophages, differentiation and function after MCP-1 an anti-inflammatory phenotype of the renal macrophages. For example, the to was reduced, is as heparanase expression in glomerular endothelial cells and M. M. van Rabelink T.J. I. M. van der J. is for the development of acute experimental J Pathol. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar was a reduction in the release of cathepsin the enzyme that has been shown to be in the development of diabetic M. H. van Rabelink T.J. T. van der J. L is for the development of early experimental diabetic Int. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar cathepsin L in during 2011; PubMed Scopus Google Scholar to the of of macrophages. also been shown to the CCR2 E. S. F. G. D. G. R. D. S. G. G. of the monocyte chemoattractant chemokine receptor 2 system on expression in streptozotocin-treated mice and human PubMed Scopus Google Scholar that MCP-1 could glomerular filtration barrier function as In however, MCP-1 inhibition of and the number of In podocytes, cathepsin L is involved in of M. H. van Rabelink T.J. T. van der J. L is for the development of early experimental diabetic Int. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. S. S. J. K. J. P. The of kidney is a of the effect of 2008; PubMed Scopus Google Scholar was not by MCP-1 suggest that not albuminuria by podocyte function. to be a treatment effect on in at weeks after of treatment. heparanase expression was still reduced and the glycocalyx and heparan was still further the that the effects of MCP-1 inhibition are of and are to glomerular findings on treatment were also in the study in emapticap effects on and without were on of J. Eulberg D. Beyer D. Baumann M. Saudek F. Valkusz Z. Wiecek A. Haller H. Emapticap Study GroupC-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria.Nephrol Dial Transplant. 2017; 32: 307-315Crossref PubMed Google Scholar The presence of in the urine to weeks after treatment further a effect of MCP-1 blockade has potential in the treatment of diabetic nephropathy, therapeutic are still is by observations in human diabetic nephropathy, increased renal and MCP-1 levels been T. K. N. Y. K. Shimizu M. K. M. H. N. T. K. H. of monocyte chemoattractant protein-1 in of human diabetic Int. Full Text Full Text PDF PubMed Scopus Google Scholar and a mechanism of for recent observations in human diabetic nephropathy, blockade of MCP-1 reduced J. Eulberg D. Beyer D. Baumann M. Saudek F. Valkusz Z. Wiecek A. Haller H. Emapticap Study GroupC-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria.Nephrol Dial Transplant. 2017; 32: 307-315Crossref PubMed Google Scholar In we persistent of the glomerular endothelial glycocalyx in diabetic nephropathy with MCP-1 suggest that with macrophage function the of the glycocalyx by in We J. for the of the van der for and for and for analysis of and and and and the and and and the and the for and and the and the is the of as to the in the study and for the of the and the of the cell of for CCR2 was in peripheral blood renal cells and is as index for expression in proinflammatory and and reduces cathepsin L in macrophages. The murine macrophage cell was and as in with and The cell was to the of to macrophage cathepsin L macrophages, cells were by in for to the macrophages were with monocyte chemotactic protein-1 with without for in of cells was treated with after cathepsin L was in cell Data are as to macrophages treated with