The role of the complement system in diabetic nephropathy

Key Points

  • Diabetic nephropathy has severe individual and societal consequences, owing to its high morbidity, mortality and health-care costs

  • Despite the availability of anti-glycaemic, renoprotective and antihypertensive agents, diabetes mellitus remains the most common cause of end-stage renal disease in developed countries

  • New biomarkers that can identify patients at risk of diabetic nephropathy are needed, as well as new agents that directly target the pathogenic pathways of diabetic nephropathy

  • Growing evidence suggests that the complement system has a pathogenic role in the development of diabetic nephropathy

  • Mannose-binding protein is a strong biomarker of diabetic nephropathy in patients with type 1 diabetes mellitus (T1DM) and T2DM; H-ficolin might be useful to identify patients with T1DM at risk of persistent microalbuminuria

  • Inhibiting specific components of the complement system might be an effective therapeutic strategy to treat diabetic nephropathy

Abstract

The development of type 1 and type 2 diabetes mellitus has a substantial negative impact on morbidity and mortality and is responsible for substantial individual and socioeconomic costs worldwide. One of the most serious consequences of diabetes mellitus is the development of diabetic angiopathy, which manifests clinically as microvascular and macrovascular complications. One microvascular complication, diabetic nephropathy, is the most common cause of end-stage renal disease in developed countries. Although several available therapeutic interventions can delay the onset and progression of diabetic nephropathy, morbidity associated with this disease remains high and new therapeutic approaches are needed. In addition, not all patients with diabetes mellitus will develop diabetic nephropathy and thus new biomarkers are needed to identify individuals who will develop this life-threatening disease. An increasing body of evidence points toward a role of the complement system in the pathogenesis of diabetic nephropathy. For example, circulating levels of mannose-binding lectin (MBL), a pattern recognition molecule of the innate immune system, have emerged as a robust biomarker for the development and progression of this disease, and evidence suggests that MBL, H-ficolin, complement component C3 and the membrane attack complex might contribute to renal injury in the hyperglycaemic mileu. New approaches to modulate the complement system might lead to the development of new agents to prevent or slow the progression of diabetic nephropathy.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The complement system and its targets.
Figure 2: The pathogenic role of complement in hyperglycaemia-induced renal injury.

References

  1. 1

    International Diabetes Federation. IDF Diabetes Atlas, Seventh Edition. Diabetes Atlas http://www.diabetesatlas.org/resources/2015-atlas.html (2015).

  2. 2

    Schrijvers, B. F., De Vriese, A. S. & Flyvbjerg, A. From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr. Rev. 25, 971–1010 (2004).

    CAS  Article  PubMed  Google Scholar 

  3. 3

    Pfützner, A. & Forst, T. High-sensitivity C-reactive protein as cardiovascular risk marker in patients with diabetes mellitus. Diabetes Technol. Ther. 8, 28–36 (2006).

    Article  PubMed  Google Scholar 

  4. 4

    Schalkwijk, C. G. et al. Plasma concentration of C-reactive protein is increased in type I diabetic patients without clinical macroangiopathy and correlates with markers of endothelial dysfunction: evidence for chronic inflammation. Diabetologia 42, 351–357 (1999).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Flyvbjerg, A. Diabetic angiopathy, the complement system and the tumour necrosis factor superfamily. Nat. Rev. Endocrinol. 6, 94–101 (2010).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Wada, J. & Makino, H. Innate immunity in diabetes and diabetic nephropathy. Nat. Rev. Nephrol. 12, 13–26 (2016).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Molitch, M. E. et al. Diabetic kidney disease: a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 87, 20–30 (2015).

    Article  PubMed  Google Scholar 

  8. 8

    United States Renal Data System. 2014 annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. https://www.usrds.org/2014/view/ (2014).

  9. 9

    Assogba, F. G. et al. Trends in the epidemiology and care of diabetes mellitus-related end-stage renal disease in France, 2007–2011. Diabetologia 57, 718–728 (2014).

    Article  PubMed  Google Scholar 

  10. 10

    Van Dijk, P. R. et al. Incidence of renal replacement therapy for diabetic nephropathy in the Netherlands: Dutch diabetes estimates (DUDE)-3. BMJ Open 5, e005624 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    Toppe, C. et al. Renal replacement therapy due to type 1 diabetes; time trends during 1995–2010 — a Swedish population based register study. J. Diabetes Complicat. 28, 152–155 (2014).

    Article  PubMed  Google Scholar 

  12. 12

    Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977–986 (1993).

  13. 13

    UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837–853 (1998).

  14. 14

    Gaede, P., Lund-Andersen, H., Parving, H.-H. & Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Turner, M. W. The role of mannose-binding lectin in health and disease. Mol. Immunol. 40, 423–429 (2003).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Thiel, S. et al. A second serine protease associated with mannan-binding lectin that activates complement. Nature 386, 506–510 (1997).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Law, S. K. A. & Reid, K. B. M. Complement 2nd edn (IRL Press at Oxford Univ. Press, 1995).

    Google Scholar 

  18. 18

    Mason, C. P. & Tarr, A. W. Human lectins and their role in viral infections. Molecules 20, 2229–2271 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Keshi, H. et al. Identification and characterization of a novel human collectin CL-K1. Microbiol. Immunol. 50, 1001–1013 (2006).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Nomura, A. et al. Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis. Am. J. Pathol. 151, 539–547 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Nangaku, M. et al. Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J. Am. Soc. Nephrol. 10, 2323–2331 (1999).

    CAS  PubMed  Google Scholar 

  22. 22

    Nangaku, M. et al. C6 mediates chronic progression of tubulointerstitial damage in rats with remnant kidneys. J. Am. Soc. Nephrol. 13, 928–936 (2002).

    CAS  PubMed  Google Scholar 

  23. 23

    Morita, Y. et al. Complement activation products in the urine from proteinuric patients. J. Am. Soc. Nephrol. 11, 700–707 (2000).

    CAS  PubMed  Google Scholar 

  24. 24

    Fortpied, J., Vertommen, D. & Van Schaftingen, E. Binding of mannose-binding lectin to fructosamines: a potential link between hyperglycaemia and complement activation in diabetes. Diabetes Metab. Res. Rev. 26, 254–260 (2010).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Fan, W. X. et al. Activation of the lectin complement pathway on human renal glomerular endothelial cells triggered by high glucose and mannose-binding lectin. Afr. J. Biotechnol. 10, 18539–18549 (2011).

    CAS  Google Scholar 

  26. 26

    Acosta, J. et al. Molecular basis for a link between complement and the vascular complications of diabetes. Proc. Natl Acad. Sci. USA 97, 5450–5455 (2000).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Qin, X. et al. Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes 53, 2653–2661 (2004).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Østergaard, J. et al. Mannose-binding lectin deficiency attenuates renal changes in a streptozotocin-induced model of type 1 diabetes in mice. Diabetologia 50, 1541–1549 (2007).

    Article  PubMed  Google Scholar 

  29. 29

    Østergaard, J. A. et al. Mannan-binding lectin in diabetic kidney disease: the impact of mouse genetics in a type 1 diabetes model. Exp. Diabetes Res. 2012, 678381 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Østergaard, J. A. et al. Diabetes-induced changes in mannan-binding lectin levels and complement activation in a mouse model of type 1 diabetes. Scand. J. Immunol. 77, 187–194 (2013).

    Article  PubMed  Google Scholar 

  31. 31

    Østergaard, J. A. et al. Increased autoreactivity of the complement-activating molecule mannan-binding lectin in a type 1 diabetes model. J. Diabetes Res. 2016, 1825738 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Hansen, T. K. et al. Elevated levels of mannan-binding lectin in patients with type 1 diabetes. J. Clin. Endocrinol. Metab. 88, 4857–4861 (2003).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Saraheimo, M. et al. Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy. Diabetologia 48, 198–202 (2005).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Hansen, T. K. et al. Association between mannose-binding lectin and vascular complications in type 1 diabetes. Diabetes 53, 1570–1576 (2004).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Østergaard, J. A. et al. Increased all-cause mortality in patients with type 1 diabetes and high-expression mannan-binding lectin genotypes: a 12-year follow-up study. Diabetes Care 38, 1898–1903 (2015).

    Article  PubMed  Google Scholar 

  36. 36

    Kaunisto, M. A. et al. Elevated MBL concentrations are not an indication of association between the MBL2 gene and type 1 diabetes or diabetic nephropathy. Diabetes 58, 1710–1714 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Hovind, P. et al. Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study. Diabetes 54, 1523–1527 (2005).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Hansen, T. K. et al. Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes. Diabetologia 53, 1517–1524 (2010).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Zhao, S. Q. & Hu, Z. Mannose-binding lectin and diabetic nephropathy in type 1 diabetes. J. Clin. Lab. Anal. 30, 345–350 (2016).

    CAS  Article  PubMed  Google Scholar 

  40. 40

    Berger, S. P. et al. Low pretransplantation mannose-binding lectin levels predict superior patient and graft survival after simultaneous pancreas-kidney transplantation. J. Am. Soc. Nephrol. 18, 2416–2422 (2007).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Bijkerk, R. et al. Simultaneous pancreas-kidney transplantation in patients with type 1 diabetes reverses elevated MBL levels in association with MBL2 genotype and VEGF expression. Diabetologia 59, 853–858 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Hansen, T. K. et al. Mannose-binding lectin and mortality in type 2 diabetes. Arch. Intern. Med. 166, 2007–2013 (2006).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Elawa, G. et al. The predictive value of serum mannan-binding lectin levels for diabetic control and renal complications in type 2 diabetic patients. Saudi Med. J. 32, 784–790 (2011).

    PubMed  Google Scholar 

  44. 44

    Zhang, N. et al. Association of levels of mannose-binding lectin and the MBL2 gene with type 2 diabetes and diabetic nephropathy. PLoS ONE 8, e83059 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Guan, L. Z., Tong, Q. & Xu, J. Elevated serum levels of mannose-binding lectin and diabetic nephropathy in type 2 diabetes. PLoS ONE 10, e0119699 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Holt, C. B. et al. Ficolin B in diabetic kidney disease in a mouse model of type 1 diabetes. Mediators Inflamm. 2015, 653260 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Østergaard, J. A. et al. Association of the pattern recognition molecule H-ficolin with incident microalbuminuria in an inception cohort of newly diagnosed type 1 diabetic patients: an 18 year follow-up study. Diabetologia 57, 2201–2207 (2014).

    Article  PubMed  Google Scholar 

  48. 48

    Jenny, L. et al. Plasma levels of mannan-binding lectin-associated serine proteases MASP-1 and MASP-2 are elevated in type 1 diabetes and correlate with glycaemic control. Clin. Exp. Immunol. 180, 227–232 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Mauer, S. M. et al. Pancreatic islet transplantation. Effects on the glomerular lesions of experimental diabetes in the rat. Diabetes 23, 748–753 (1974).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Mauer, S. M. et al. Studies of the rate of regression of the glomerular lesions in diabetic rats treated with pancreatic islet transplantation. Diabetes 24, 280–285 (1975).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Lee, C. S. et al. Renal transplantation in diabetes mellitus in rats. J. Exp. Med. 139, 793–800 (1974).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Xiao, X. et al. Cellular and humoral immune responses in the early stages of diabetic nephropathy in NOD mice. J. Autoimmun. 32, 85–93 (2009).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Yang, L. et al. Inflammatory gene expression in OVE26 diabetic kidney during the development of nephropathy. Nephron Exp. Nephrol. 119, e8–e20 (2011).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Wehner, H. et al. Glomerular changes in mice with spontaneous hereditary diabetes. Lab. Invest. 27, 331–340 (1972).

    CAS  PubMed  Google Scholar 

  55. 55

    Kelly, K. J., Liu, Y., Zhang, J., Dominguez, J. H. Renal C3 complement component: feed forward to diabetic kidney disease. Am. J. Nephrol. 41, 48–56 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Woroniecka, K. I. et al. Transcriptome analysis of human diabetic kidney disease. Diabetes 60, 2354–2369 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Fujita, T. et al. Complement-mediated chronic inflammation is associated with diabetic microvascular complication. Diabetes Metab. Res. Rev. 29, 220–226 (2013).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Chiarelli, F., Verrotti, A., La Penna, G. & Morgese, G. Low serum C4 concentrations in type-1 diabetes mellitus. Eur. J. Pediatr. 147, 197–198 (1988).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Barnett, A. H. et al. Low plasma C4 concentrations: association with microangiopathy in insulin dependent diabetes. Br. Med. J. 289, 943–945 (1984).

    CAS  Article  Google Scholar 

  60. 60

    Cooper, M. E. et al. Low serum C4 concentrations and microangiopathy in type I and type II diabetes. Br. Med. J. 292, 801 (1986).

    CAS  Article  Google Scholar 

  61. 61

    Lhotta, K. et al. Complement C4 phenotypes in patients with end-stage renal disease. Nephron 72, 442–446 (1996).

    CAS  Article  PubMed  Google Scholar 

  62. 62

    Lhotta, K. et al. Polymorphism of complement C4 and susceptibility to IDDM and microvascular complications. Diabetes Care 19, 53–55 (1996).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Falk, R. J. et al. Neoantigen of the polymerized ninth component of complement. Characterization of a monoclonal antibody and immunohistochemical localization in renal disease. J. Clin. Invest. 72, 560–573 (1983).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Falk, R. J., Scheinman, J. I., Mauer, S. M. & Michael, A. F. Polyantigenic expansion of basement membrane constituents in diabetic nephropathy. Diabetes 32 (Suppl. 2), 34–39 (1983).

    Article  PubMed  Google Scholar 

  65. 65

    Falk, R. J. et al. Ultrastructural localization of the membrane attack complex of complement in human renal tissues. Am. J. Kidney Dis. 9, 121–128 (1987).

    CAS  Article  PubMed  Google Scholar 

  66. 66

    Uesugi, N. et al. Possible mechanism for medial smooth muscle cell injury in diabetic nephropathy: glycoxidationmediated local complement activation. Am. J. Kidney Dis. 44, 224–238 (2004).

    CAS  Article  PubMed  Google Scholar 

  67. 67

    Wada, T. & Nangaku, M. Novel roles of complement in renal diseases and their therapeutic consequences. Kidney Int. 84, 441–450 (2013).

    CAS  Article  PubMed  Google Scholar 

  68. 68

    Ghosh, P., Sahoo, R., Vaidya, A., Chorev, M. & Halperin, J. A. Role of complement and complement regulatory proteins in the complications of diabetes. Endocr. Rev. 36, 272–288 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69

    Flyvbjerg, A. in Textbook of Diabetes 5th edn (eds Holt, R. I. G., Cockram, C., Flyvbjerg, A. & Goldstein, B. J.) 543–553 (Wiley-Blackwell, 2017).

    Google Scholar 

  70. 70

    Morgan, B. P. & Harris, C. L. Complement, a target for therapy in inflammatory and degenerative diseases. Nat. Rev. Drug Discov. 14, 857–877 (2015).

    CAS  Article  PubMed  Google Scholar 

  71. 71

    Wang, H. et al. The lectin-like domain of thrombomodulin ameliorates diabetic glomerulopathy via complement inhibition. Thromb. Haemost. 108, 1141–1153 (2012).

    Article  PubMed  Google Scholar 

  72. 72

    Li, L. et al. C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease. Metabolism 64, 597–610 (2015).

    CAS  Article  PubMed  Google Scholar 

  73. 73

    Li, L. et al. C3a receptor antagonist ameliorates inflammatory and fibrotic signals in type 2 diabetic nephropathy by suppressing the activation of TGF-β/smad3 and IKBα pathway. PLoS ONE 9, e113639 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    Fujita, T. et al. Complement activation accelerates glomerular injury in diabetic rats. Nephron 81, 208–214 (1999).

    CAS  Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Allan Flyvbjerg.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Glossary

Polyol pathway

A pathway whereby aldoketo-reductase enzymes use nicotinic acid adenine dinucleotide phosphate (NADPH) to reduce sugar-derived carbonyl compounds to their respective sugar alcohols (polyols). Glucose is converted to sorbitol, and galactose to galactitol. Further, sorbitol is oxidized to fructose by sorbitol dehydrogenase, with a reduction of NAD+ to NADH. The rate-limiting step of the polyol pathway is regulated by aldose reductase.

Hexosamine pathway

A pathway whereby glucosamine-6-phosphate is made from fructose-6-phosphate and an amino group from glutamine, and glucosamine-6-phosphate is acetylated through an exchange with acetyl-coenzyme A to form N-acetylglucosamine- 6-phosphate. The 6-phosphate forms N-acetyl-glucosamine-1-phosphate through the action of an isomerase. Finally, through a reaction with uridine triphosphate, uridine diphosphate-N-acetylglucosamine is formed.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Flyvbjerg, A. The role of the complement system in diabetic nephropathy. Nat Rev Nephrol 13, 311–318 (2017). https://doi.org/10.1038/nrneph.2017.31

Download citation

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing