Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical and Experimental Nephrology
Published in: Clinical and Experimental Nephrology 6/2013

01-12-2013 | Original Article

CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations

Authors: Akinori Hara, Norihiko Sakai, Kengo Furuichi, Yoshio Sakai, Motohiro Takeya, Richard Bucala, Naofumi Mukaida, Yoh Takuwa, Kouji Matsushima, Shuichi Kaneko, Takashi Wada

Published in: Clinical and Experimental Nephrology | Issue 6/2013

Login to get access

Abstract

Background

The migration and activation of circulating profibrotic cells including fibrocytes by the action of the chemokine/chemokine receptor system has been implicated in pathological fibrogenesis. In the present study, the involvement of collagen 1 (Col1)-producing cells, CD45-positive/collagen-1-positive (CD45+/Col1+) cells originally named as fibrocytes via CC chemokine receptor 2 (CCR2), a cognate receptor of CCL2/monocyte chemoattractant protein, was examined in diabetic conditions.

Methods

Human CD45+/Col1+ cells originating from the peripheral blood of healthy volunteers were incubated with high concentrations of d-glucose or d-mannitol as an osmotic control for 12, 24 or 48 h. In addition, these cells were preincubated with CCL2 under high glucose concentrations. We also examined the effects of the inhibitors of glucose transporters (GLUTs), reactive oxygen species or CCR2 on the expression of transforming growth factor beta1 (TGF-β1), pro-α1 chain of Col1 (COL1A1), and CCL2.

Results

Stimulation of CD45+/Col1+ cells with high glucose concentrations increased the mRNA and protein levels of TGF-β1 and CCL2 and those of pro-COL1A1, and this effect was mediated in part by increased osmolality. Preincubation of the cells with cytochalasin B (a GLUT inhibitor) or N-acetylcysteine (an antioxidant) blocked the stimulatory effect of high glucose concentrations on these profibrotic molecules. In addition, preincubation of the cells with CCL2 enhanced the high glucose-induced upregulation of TGF-β1, pro-COL1A1 and CCL2 and migration of the cells, and this effect was partly inhibited by treatment with CCR2 inhibitors.

Conclusion

These results suggest that CD45+/Col1+ cells may be directly involved, in part through CCL2/CCR2 signaling, in the fibrotic process under diabetic conditions.
Literature
1.
Wada T, Shimizu M, Toyama T, Hara A, Kaneko S, Furuichi K. Clinical impact of albuminuria in diabetic nephropathy. Clin Ext Nephrol. 2012; 16(1): 96−101
2.
Parving HH, Mauer M, Ritz E. Diabetic nephropathy. In: Brenner BM editor. The kidney, 7th ed. W. B. Saunders Company, Philadelphia, 2004. pp. 1777–1818.
3.
Qian Y, Feldman E, Pennathur S, Kretzler M, Brosius FC. From fibrosis to sclerosis. Mechanisms of glomerulosclerosis in diabetic nephropathy. Diabetes. 2008;57:1439–45.PubMedCrossRef
4.
Wada T, Furuichi K, Sakai N, Iwata Y, Yoshimoto K, Shimizu M, Takeda SI, Takasawa K, Yoshimura M, Kida H, Kobayashi KI, Mukaida N, Naito T, Matsushima K, Yokoyama H. Up-regulation of MCP-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 2000;58:1492–9.PubMedCrossRef
5.
Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet. 1998;352:213–9.PubMedCrossRef
6.
Navarro-gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol. 2011;7:327–40.PubMedCrossRef
7.
Sakai N, Wada T, Furuichi K, Iwata Y, Yoshimoto K, Kitagawa K, Kokubo S, Kobayashi M, Hara A, Yamahana J, Okumura T, Takasawa K, Takeda S, Yoshimura M, Kida H, Yokoyama H. Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy. Am J Kidney Dis. 2005;45:54–65.PubMedCrossRef
8.
Wada T, Yokoyama H, Furuichi K, Kobayashi KI, Harada K, Naruto M, Su SB, Akiyama H, Mukaida N, Matsushima K. Intervention of crescentic glomerulonephritis by antibodies to monocyte chemotactic and activating factor (MCAF/MCP-1). FASEB J. 1996;10:1418–25.PubMed
9.
Wada T, Matsushima K, Kaneko S. The role of chemokines in glomerulonephritis. Front Biosci. 2008;13:3966–74.PubMedCrossRef
10.
Bucala R, Spiegel LA, Chesney J, Hogan M, Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair. Mol Med. 1994;1:71–81.PubMedPubMedCentral
11.
Wada T, Sakai N, Sakai Y, Matsushima K, Kaneko S, Furuichi K. Involvement of bone-marrow-derived cells in kidney fibrosis. Clin Exp Nephrol. 2011;15:8–13.PubMedCrossRef
12.
Moore BB, Kolodsick JE, Thannickal VJ, Cooke K, Moore TA, Hogaboam C, Wilke CA, Toews GB. CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury. Am J Pathol. 2005;166:675–84.PubMedCrossRefPubMedCentral
13.
Wada T, Sakai N, Matsushima K, Kaneko S. Fibrocytes: a new insight into kidney fibrosis. Kidney Int. 2007;72:269–73.PubMedCrossRef
14.
Sakai N, Wada T, Yokoyama H, Lipp M, Ueha S, Matsushima K, Kaneko S. Secondary lymphoid tissues chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis. Proc Natl Acad Sci USA. 2006;103:14098–103.PubMedCrossRefPubMedCentral
15.
Sakai N, Furuichi K, Shinozaki Y, Yamauchi H, Toyama T, Kitajima S, Okumura T, Kokubo S, Kobayashi M, Takasawa K, Takeda S, Yoshimura M, Kaneko S, Wada T. Fibrocytes are involved in the pathogenesis of human chronic kidney disease. Hum Pathol. 2010;41:672–8.PubMedCrossRef
16.
Pilling D, Fan T, Huang D, Kaul B, Gomer RH. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts. PLoS One. 2009;4:e7475.PubMedCrossRefPubMedCentral
17.
18.
Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediates fibrosis. J Clin Invest. 2004;114:438–46.PubMedPubMedCentral
19.
Sakai N, Wada T, Matsushima K, Bucala R, Iwai M, Horiuchi M, Kaneko S. The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes. J Hypertens. 2008;26:780–90.PubMedCrossRef
20.
Lachaal M, Rampal AL, Lee W, Shi Y, Jung CY. GLUT1 transmembrane glucose pathway. Affinity labeling with a transportable d-glucose diazirine. J Biol Chem. 1996;271:5225–30.PubMedCrossRef
21.
Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M, Kouyama R, Kobayashi Y, Nitta N, Yasuda K, Hirata Y, Kuziel WA, Takeya M, Kanegasaki S, Kamei Y, Ogawa Y. Role of CC chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue. J Biol Chem. 2008;283:35715–23.PubMedCrossRef
22.
Sakai N, Wada T, Furuichi K, Shimizu K, Kokubo S, Hara A, Yamahana J, Okumura T, Matsushima K, Yokoyama H, Kaneko S. MCP-1/CCR2-dependent loop for fibrogenesis in human peripheral CD14-positive monocytes. J Leukoc Biol. 2006;79:555–63.PubMedCrossRef
23.
Kitagawa K, Wada T, Furuichi K, Hashimoto H, Ishiwata Y, Asano M, Takeya M, Kuziel WA, Matsushima K, Mukaida N, Yokoyama H. Blockade of CCR2 ameliorates progressive fibrosis in kidney. Am J Pathol. 2004;165:237–46.PubMedCrossRefPubMedCentral
24.
Schröppel B, Fischereder M, Wiese P, Segerer S, Huber S, Kretzler M, Heiss P, Sitter T, Schlöndorff D. Expression of glucose transporters in human peritoneal mesothelial cells. Kidney Int. 1998;53:1278–87.PubMedCrossRef
25.
Strieter RM, Keeley EC, Hughes MA, Burdick MD, Mehrad B. The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis. J Leukoc Biol. 2009;86:1111–8.PubMedCrossRefPubMedCentral
26.
Calder PC, Dimitriadis G, Newsholme P. Glucose metabolism in lymphoid and inflammatory cells and tissues. Curr Opin Clin Nutr Metab Care. 2007;10:531–40.PubMedCrossRef
27.
Maratou E, Dimitriadis G, Kollias A, Boutati E, Lambadiari V, Mitrou P, Raptis SA. Glucose transporter expression on the plasma membrane of resting and activated white blood cells. Eur J Clin Invest. 2007;37:282–90.PubMedCrossRef
28.
Takaishi H, Taniguchi T, Takahashi A, Ishikawa Y, Yokoyama M. High glucose accelerates MCP-1 production via p38 MAPK in vascular endothelial cells. Biochem Biophys Res Commun. 2003;305:122–8.PubMedCrossRef
29.
Shanmugam N, Reddy MA, Guha M, Natarajan R. High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes. 2003;52:1256–64.PubMedCrossRef
30.
Morohoshi M, Fujisawa K, Uchimura I, Numano F. Glucose-dependent interleukin-6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes. 1996;45:954–9.PubMedCrossRef
31.
Janssen U, Sowa E, Marchand P, Floege J, Phillips AO, Radeke HH. Differential expression of MCP-1 and its receptor CCR2 in glucose primed human mesangial cells. Nephron. 2002;92:797–806.PubMedCrossRef
32.
Wong TYH, Phillips AO, Witowski J, Topley N. Glucose-mediated induction of TGF-β1 and MCP-1 in mesothelial cells in vitro is osmolality and polyol pathway dependent. Kidney Int. 2003;62:1404–16.CrossRef
33.
Mine S, Okada Y, Tanikawa T, Kawahara C, Tabata T, Tanaka Y. Increased expression levels of monocyte CCR2 and monocyte chemoattractant protein-1 in patients with diabetes mellitus. Biochem Biophys Res Commun. 2006;344:780–5.PubMedCrossRef
34.
Shin CS, Moon BS, Park KS, Kim SY, Park SJ, Chung MH, Lee HK. Serum 8-hydroxy-guanine levels are increased in diabetic patients. Diabetes Care. 2001;24:733–7.PubMedCrossRef
35.
Cvetković T, Mitić B, Lazarević G, Vlahović P, Antić S, Stefanović V. Oxidative parameters as possible urine markers in patients with diabetic nephropathy. J Diabetes Complicat. 2009;23:337–42.PubMedCrossRef
36.
Pedersen SF, Kapus A, Hoffmann EK. Osmosensory mechanisms in cellular and systemic volume regulation. J Am Soc Nephrol. 2011;22:1587–97.PubMedCrossRef
37.
Hong KM, Burdick MD, Phillips RJ, Heber D, Strieter RM. Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice. FASEB J. 2005;19:2029–31.PubMed
38.
Tarabra E, Giunti S, Barutta F, Salvidio G, Burt D, Deferrari G, Gambino R, Vergola D, Pinach S, Perin PC, Camussi G, Gruden G. Effect of the monocyte chemoattractant protein-1/CC chemokine receptor 2 system on nephrin expression in streptozotocin-treated mice and human cultured podocytes. Diabetes. 2009;58:2109–18.PubMedCrossRefPubMedCentral
39.
Bellini A, Mattoli S. The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses. Lab Invest. 2007;87:858–70.PubMedCrossRef
Metadata
Title
CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations
Authors
Akinori Hara
Norihiko Sakai
Kengo Furuichi
Yoshio Sakai
Motohiro Takeya
Richard Bucala
Naofumi Mukaida
Yoh Takuwa
Kouji Matsushima
Shuichi Kaneko
Takashi Wada
Publication date
01-12-2013
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 6/2013
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-013-0796-6

Other articles of this Issue 6/2013

Clinical and Experimental Nephrology 6/2013 Go to the issue

Images in Nephrology

Pleural effusion in peritoneal dialysis: overload or leakage?

Original Article

Long-term observations of clinicopathological characteristics and outcome of Japanese patients with pauci-immune crescentic glomerulonephritis

Original Article

Japan Diabetic Nephropathy Cohort Study: study design, methods, and implementation

Original Article

Reduced podocin expression in minimal change disease and focal segmental glomerulosclerosis is related to the level of proteinuria

Original Article

The intercalated cells of the mouse kidney OMCDis are the target of the vasopressin V1a receptor axis for urinary acidification

Original Article

Albuminuria is an independent predictor of all-cause and cardiovascular mortality in the Japanese population: the Takahata study
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits