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Nephrol Dial Transplant (2003) 18: 457-459
© 2003 European Renal Association-European Dialysis and Transplant Association

Editorial Comments

Monocyte chemoattractant protein-1: does it play a role in diabetic nephropathy?

Takashi Wada, Hitoshi Yokoyama, Kouji Matsushima1 and Ken-ichi Kobayashi

Department of Gastroenterology and Nephrology, Graduate School of Medical Science and Division of Blood Purification, Kanazawa University, Kanazawa and 1 Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo, Tokyo, Japan

Keywords: CCR2; chemokine; diabetic nephropathy; macrophage/monocyte; MCP-1; TGF-ß

Introduction

Both metabolic and haemodynamic pathways impact on the progression of diabetic nephropathy [1,2]. Chronic hyperglycaemia, advanced glycation end (AGE) products, increase of sorbitol, activation of protein kinase C (PKC), glomerular hypertension and genetic susceptibility have been identified as risk factors in the progression of diabetic nephropathy [2]. Moreover, infiltration of the diseased kidneys by inflammatory cells such as monocytes/macrophages (M{phi}) is a hallmark of diabetic nephropathy [3,4]. Infiltrated M{phi} release lysosomal enzymes, nitrous oxide (NO), reactive oxygen intermediates (ROI) and transforming growth factor (TGF)-ß, which play an essential role in renal damage [2,5]. A chemokine, monocyte chemoattractant protein (MCP)-1, also termed monocyte chemotactic and activating factor (MCAF) or CCL2, is secreted by mononuclear cells and various non-leukocytic cells including renal resident cells. In experimental glomerulonephritis models [6–8] and human nephritis [9–11] it is thought to play an important role in the pathogenesis of crescent formation and progressive tubulointerstitial lesions via M{phi} recruitment and activation.

In addition to these inflammatory renal diseases, recent studies suggest that MCP-1 is also involved in diabetic nephropathy.

In this editorial comment we focus on (i) MCP-1 and its cognate receptor, CCR2 in human diabetic nephropathy, and (ii) in vitro and in vivo studies of the role of MCP-1/CCR2 in the pathogenesis of diabetic nephropathy. The findings suggest interventions targeting the MCP-1/CCR2 systems as potential strategies to treat diabetic nephropathy.

MCP-1/CCR2 in human diabetic nephropathy

Up-regulation of locally produced MCP-1 may be involved in advanced tubulointerstitial lesions in diabetic patients with nephrotic syndrome through M{phi} recruitment and activation [4,12]. This idea is based on the findings that: (i) urinary MCP-1 levels were significantly elevated in patients with diabetic nephrotic syndrome and advanced tubulointerstitial lesions (tubular atrophy, fibrosis, arteriolosclerosis); (ii) urinary levels of MCP-1 were correlated with CD68-positive M{phi} in the interstitium; (iii) MCP-1-positive cells were detected in advanced tubulointerstitial lesions of diabetic nephropathy by both immunohistochemical and in situ hybridization analyses; (iv) urinary MCP-1 excretion was correlated with the number of MCP-1-positive cells in the interstitium of renal biopsy specimens; and (v) patients with minimal change nephrotic syndrome showed lower levels of urinary MCP-1, suggesting that massive proteinuria by itself does not necessarily increase urinary MCP-1 levels. We previously reported that MCP-1 plays a pivotal role in the genesis of progressive tubulointerstitial damage and promotes renal dysfunction in crescentic glomerulonephritis, human lupus nephritis and IgA nephropathy as well as in an experimental glomerulonephritis model [13]. Collectively, these findings suggest that up-regulation of MCP-1 may be a common regulatory pathway involved in the progressive diabetic nephropathy as well as inflammatory renal diseases.

Urinary levels of MCP-1 increased progressively in diabetic patients with advancing glomerular lesions, although MCP-1 was not detected in diseased glomeruli and no correlation was found between the number of CD68-positive cells in glomeruli and urinary levels of MCP-1. These results might be explained by the close association between glomerular and tubulointerstitial lesions in diabetic nephropathy. MCP-1 may also have an indirect impact on glomerular lesions via the progression of arteriolosclerosis (nephrosclerosis).

In contrast to MCP-1, little is known about the role of CCR2 in human diabetic nephropathy. CCR2-positive cells are present in diseased kidneys with diabetic nephropathy (T. Wada, H. Yokoyama, K. Matsushima and K. Kobayashi, unpublished results). The number of interstitial CCR2-positive cells in patients with diabetic nephropathy closely reflected the extent and intensity of interstitial fibrosis and tubular atrophy as well as urinary levels of MCP-1. Nakajima et al. [14] recently reported on the association of chemokine receptor polymorphisms with diabetic nephropathy in patients with type 2 diabetes in Japan. A polymorphism of CCR2 coding region V641 was documented in Japanese patients, but further studies are needed to establish the significance, if any, of the CCR2 polymorphism in the progression of diabetic nephropathy. Taken together, these observations suggest that MCP-1/CCR2 may be involved in the development of advanced human diabetic nephropathy, especially in the formation of tubulointerstitial lesions through M{phi} recruitment and activation (Figure 1Go).



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  		Fig. 1.  MCP-1: the common regulatory molecule of chronic inflammation resulting in renal sclerosis/fibrosis.

 

In vitro and in vivo expression of MCP-1/CCR2 in diabetic conditions

It is likely that the pathogenesis of diabetic nephropathy involves an interaction of metabolic and haemodynamic factors [5]. Hyperglycaemia is followed by M{phi} recruitment that contributes to the molecular and structural events leading to glomerulosclerosis [15,16]. A high glucose concentration in the culture medium stimulates the expression of MCP-1 in human mesangial cells, and high glucose rapidly activates nuclear factor-{kappa}B (NF-{kappa}B) in mesangial cells through PKC and reactive oxygen species [17,18]. In addition, AGE have been implicated in the pathogenesis of diabetic nephropathy. Supporting this notion, AGE directly induces MCP-1 expression in human mesangial cells [19]. Interestingly, Pugliese et al. [20] demonstrated an acceleration of diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice, suggesting that the galectin-3-regulated AGE receptor pathway is operating in vivo and protects against AGE-induced tissue injury, in contrast to RAGE which aggravates injury. Moreover, relevant metabolic factors include increased formation of polyols, oxidant stress and activation of PKC in addition to glucose-dependent pathways such as advanced glycation [5,21]. Indeed, oxidatively modified lipoproteins found in diabetic plasma stimulate MCP-1 gene expression in endothelial cells [22].

Glomerular filtration of growth factors, such as recombinant human TGF-ß and recombinant human hepatocyte growth factor (HGF), increased MCP-1, regulated upon activation, normal T cell expressed and secreted (RANTES, CCL5) in the interstitium [23]. These apical signals might be translated into basolateral events that are recognized by cells in the interstitium. In turn, they stimulate interstitial myofibroblasts via M{phi} and lead to accumulation of extracellular matrix proteins and progressive interstitial fibrosis [23]. Concomitantly, MCP-1 mediates collagen deposition in experimental glomerulonephritis by TGF-ß [24]. Thus far, TGF-ß has been thought to be a key factor in the progression of glomerular and tubulointerstitial lesions [25]. Therefore, once glomerular TGF-ß is activated by various stimuli, MCP-1 may be up-regulated at least in the interstitium. MCP-1 may then recruit T cells and M{phi} into the kidneys, thereby perpetuating progressive diabetic nephropathy.

Angiotensin II-dependent pathways leading to MCP-1 up-regulation have been shown to play an important role in the genesis of glomerular and tubulointerstitial damage [26]. Kato et al. [27] demonstrated that glomerular M{phi} recruitment in streptozotocin-treated rats is largely determined by angiotensin-stimulated MCP-1 expression [27]. They concluded that activation of the renin-angiotensin system is an important determinant of local MCP-1 expression, either directly or indirectly through glomerular haemodynamic effects. These findings implicate M{phi} recruitment and activation in the pathogenesis of early diabetic glomerular injury. Alternatively, massive proteinuria might induce tubular epithelial cells to activate lysosome and antigen presentation followed by the activation of helper T cells in the interstitium [28]. However, at least concerning human MCP-1, proteinuria itself did not increase urinary levels of MCP-1. Taken together, once endothelial cells, tubular epithelial cells and interstitial infiltrates have been activated by some metabolic and/or haemodynamic process, these cells produce MCP-1, which may be involved in the progression of advanced diabetic nephropathy.

In experimental models of diabetic nephropathy, MCP-1 is expressed in the glomeruli [27], although in humans MCP-1-positive cells are detected mainly in the interstitium. The apparent discrepancy between these findings could be explained as follows: (i) activated renal interstitial cells might be more prone to produce MCP-1 than glomerular cells; (ii) the findings may be an artifact due to the detection limits of immunohistochemical analysis; and (iii) there might be differences between human diabetic renal diseases and experimental animal models. Further studies will be required to clarify the roles of M{phi} via MCP-1/CCR2 in the pathogenesis of progressive glomerular and interstitial lesions in diabetic nephropathy.

Anti-MCP-1/CCR2 treatments: novel therapeutic intervention for diabetic nephropathy?

Few reports have focused on MCP-1/CCR2 as the therapeutic targets for diabetic nephropathy. Kato et al. [27] assessed expression of genes regulating monocyte transmigration in the glomeruli of diabetic rats. The time-dependent increase of MCP-1 expression was dramatically suppressed by treatment with the angiotensin-converting enzyme inhibitor enalapril or the AT1 receptor antagonist candesartan and it was closely associated with effects on proteinuria and glomerular M{phi} number [27]. However, whether the manipulation of MCP-1/CCR2 is beneficial or harmful with respect to the progression of human and experimental diabetic nephropathy remains to be investigated.

Concluding remarks and future directions

The MCP-1/CCR2 system is involved in the pathogenesis of diabetic nephropathy. We can answer the above question ‘Does MCP-1 play a role in diabetic nephropathy?’ in the affirmative. This suggests that interventions targeting the chemokine/chemokine receptor systems may be a promising strategy in diabetic nephropathy. A number of chemokine receptor antagonists is currently under development. The selective blockade of chemokines/chemokine receptor systems, particularly the MCP-1/CCR2 system, may be useful in the treatment of diabetic nephropathy in the future.

Notes

Correspondence and offprint requests to: Dr Takashi Wada, MD, PhD, Department of Gastroenterology and Nephrology, Graduate School of Medical Science and Division of Blood Purification, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. Email: twada{at}medf.m.kanazawa-u.ac.jp Back

References

  1. Ritz E. Advances in nephrology: successes and lessons from diabetes mellitus. Nephrol Dial Transplant2001; 16 [Suppl 7]:46–50[Medline]
  2. Parving HH, Osterby R, Ritz E. Diabetic nephropathy. In: Brenner BM, ed. The Kidney, 6th edn. W. B. Saunders Company, Philadelphia:2000;1731–1773
  3. Furuta T, Saito T, Ootaka T et al. The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis1993; 21:480–485[Web of Science][Medline]
  4. Wada T, Furuichi K, Sakai N et al. Up-regulation of MCP-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int2000; 58:1492–1498[CrossRef][Web of Science][Medline]
  5. Cooper ME. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet1998; 352:213–219[CrossRef][Web of Science][Medline]
  6. Wada T, Yokoyama H, Furuichi K et al. Intervention of crescentic glomerulonephritis by antibodies to monocyte chemotactic and activating factor (MCAF/MCP-1). FASEB J1996; 10:1418–1425[Abstract]
  7. Tang WW, Yin S, Witter AJ et al. Chemokine gene expression in anti-glomerular basement membrane antibody glomerulonephritis. Am J Physiol1995; 263:F323–F330
  8. Natori Y, Sekiguchi M, Ou Z et al. Gene expression of CC chemokines in experimental crescentic glomerulonephritis (CGN). Clin Exp Immunol1997; 109:143–148[CrossRef][Medline]
  9. Wada T, Furuichi K, Segawa C et al. MIP-1{alpha} and MCP-1 contribute crescents and interstitial lesions in human crescentic glomerulonephritis. Kidney Int1999; 56:995–1003[CrossRef][Web of Science][Medline]
  10. Wada T, Yokoyama H, Su SB et al. Monitoring urinary levels of monocyte chemotactic and activating factor reflects disease activity of lupus nephritis. Kidney Int1996; 49:761–767[Web of Science][Medline]
  11. Yokoyama H, Wada T, Furuichi K et al. Urinary levels chemokines (MCAF/MCP-1, IL-8) reflect distinct disease activities and phases of human IgA nephropathy. J Leukocyte Biol1998; 63:493–499[Abstract]
  12. Banba N, Nakamura T, Matsumura M et al. Possible relationship of monocyte chemoattractant protein-1 with diabetic nephropathy. Kidney Int2000; 58:684–690[CrossRef][Web of Science][Medline]
  13. Wada T, Yokoyama H, Matsushima K et al. Chemokines in renal diseases. Int Immunopharmacol2001; 1:637–645[CrossRef][Medline]
  14. Nakajima K, Tanaka Y, Nomiyama T et al. Chemokine receptor genotype is associated with diabetic nephropathy in Japanese with type 2 diabetes. Diabetes2002; 51:238–242[Abstract/Free Full Text]
  15. Sassy-Prigent C, Heudes D, Mandet C et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes2000; 49:466–475[Abstract]
  16. Young BA, Johnson RJ, Alpers CE et al. Cellular events in the evolution of experimental diabetic nephropathy. Kidney Int1995; 47:935–944[Web of Science][Medline]
  17. Ihm CG, Park JK, Hong SP et al. A high glucose concentration stimulates the expression of monocyte chemoattractant peptide 1 in human mesangial cells. Nephron1998; 79:33–37[CrossRef][Web of Science][Medline]
  18. Ha H, Yu MR, Choi YJ et al. Role of high glucose-induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol2002; 13:894–902[Abstract/Free Full Text]
  19. Yamagishi S, Inagaki Y, Okamoto T et al. Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human cultured mesangial cells. J Biol Chem2002; 277:20309–20315[Abstract/Free Full Text]
  20. Pugliese G, Pricci F, Iacobini C et al. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice. FASEB J2001; 15:2471–2478[Abstract/Free Full Text]
  21. Chappey O, Dosquet C, Wautier MP et al. Advanced glycation end products, oxidant stress and vascular lesions. Eur J Clin Invest1997; 27:97–108[CrossRef][Web of Science][Medline]
  22. Takahara N, Kashiwagi A, Nishio Y et al. Oxidized lipoproteins found in patients with NIDDM stimulate radical-induced monocyte chemoattractant protein-1 mRNA expression in cultured human endothelial cells. Diabetologia1997; 40:662–670[CrossRef][Web of Science][Medline]
  23. Wang SN, LaPage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int2000; 57:1002–1014[CrossRef][Web of Science][Medline]
  24. Schneider A, Panzer U, Zahner G et al. Monocyte chemoattractant protein-1 mediates collagen deposition in experimental glomerulonephritis by transforming growth factor-ß. Kidney Int1999; 56:135–144[CrossRef][Web of Science][Medline]
  25. Border WA, Noble NA. TGF-beta in kidney fibrosis: a target for gene therapy. Kidney Int1997; 51:1388–1396[Web of Science][Medline]
  26. Ruiz-Ortega M, Bustos C, Hernandez-Presa MA et al. Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. J Immunol1998; 161:430–439[Abstract/Free Full Text]
  27. Kato S, Luyckx VA, Ots M et al. Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats. Kidney Int1999; 56:1037–1048[CrossRef][Web of Science][Medline]
  28. Wang Y, Chen J, Chen L et al. Induction of monocyte chemoattractant protein-1 in proximal tubule cells by urinary protein. J Am Soc Nephrol1997; 8:1537–1545[Abstract]

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