Top

Diabetologia

Published in:

01-01-2012 | Article

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Authors: T. Zhou, X. He, R. Cheng, B. Zhang, R. R. Zhang, Y. Chen, Y. Takahashi, A. R. Murray, K. Lee, G. Gao, J-x. Ma

Published in: Diabetologia | Issue 1/2012

Abstract

Aims/hypothesis

The wingless-type MMTV integration site (WNT) pathway mediates multiple physiological and pathological processes, such as inflammation, angiogenesis and fibrosis. The aim of this study was to investigate whether canonical WNT signalling plays a role in the pathogenesis of diabetic nephropathy.

Methods

Expression of WNT ligands and frizzled receptors in the canonical WNT pathway in the kidney was compared at the mRNA level using real-time RT-PCR between Akita mice, streptozotocin-induced diabetic rats and db/db mice and their respective non-diabetic controls. Renal function was evaluated by measuring the urine albumin excretion. Human renal proximal tubular epithelial cells were treated with high-glucose medium and 4-hydroxynonenal (HNE). Levels of β-catenin, connective tissue growth factor and fibronectin were determined by western blot analysis.

Results

Some of the WNT ligands and frizzled receptors showed increased mRNA levels in the kidneys of Akita mice, streptozotocin-induced diabetic rats and db/db mice compared with their non-diabetic controls. Renal levels of β-catenin and WNT proteins were upregulated in these diabetic models. Lowering the blood glucose levels by insulin attenuated the activation of WNT signalling in the kidneys of Akita mice. In cultured human renal proximal tubular epithelial cells, both high glucose and HNE activated WNT signalling. Inhibition of WNT signalling with a monoclonal antibody blocking LDL-receptor-related protein 6 ameliorated renal inflammation and fibrosis and reduced proteinuria in Akita mice.

Conclusions/interpretation

The WNT pathway is activated in the kidneys of models of both type 1 and 2 diabetes. Dysregulation of the WNT pathway in diabetes represents a new pathogenic mechanism of diabetic nephropathy and renders a new therapeutic target.

Available only for authorised users

Chiarelli F, Gaspari S, Marcovecchio ML (2009) Role of growth factors in diabetic kidney disease. Horm Metab Res 41:585–593PubMedCrossRef

Fioretto P, Mauer M (2007) Histopathology of diabetic nephropathy. Semin Nephrol 27:195–207PubMedCrossRef

Kanwar YS, Wada J, Sun L et al (2008) Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood) 233:4–11CrossRef

Nangaku M (2004) Mechanisms of tubulointerstitial injury in the kidney: final common pathways to end-stage renal failure. Intern Med 43:9–17PubMedCrossRef

Phillips AO, Steadman R (2002) Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. Histol Histopathol 17:247–252PubMed

Ban CR, Twigg SM (2008) Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag 4:575–596PubMed

Wodarz A, Nusse R (1998) Mechanisms of Wnt signalling in development. Annu Rev Cell Dev Biol 14:59–88PubMedCrossRef

Liu C, Li Y, Semenov M et al (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847PubMedCrossRef

He X, Semenov M, Tamai K, Zeng X (2004) LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signalling: arrows point the way. Development 131:1663–1677PubMedCrossRef

10.

Si W, Kang Q, Luu HH et al (2006) CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 26:2955–2964PubMedCrossRef

11.

Chen Y, Hu Y, Zhou T et al (2009) Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models. Am J Pathol 175:2676–2685PubMedCrossRef

12.

Romero-Aroca P, Mendez-Marin I, Baget-Bernaldiz M, Fernendez-Ballart J, Santos-Blanco E (2010) Review of the relationship between renal and retinal microangiopathy in diabetes mellitus patients. Curr Diabetes Rev 6:88–101PubMedCrossRef

13.

Pulkkinen K, Murugan S, Vainio S (2008) Wnt signalling in kidney development and disease. Organogenesis 4:55–59PubMedCrossRef

14.

He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y (2009) Wnt/beta-catenin signalling promotes renal interstitial fibrosis. J Am Soc Nephrol 20:765–776PubMedCrossRef

15.

Lancaster MA, Gleeson JG (2010) Cystic kidney disease: the role of Wnt signalling. Trends Mol Med 16:349–360PubMedCrossRef

16.

Dai C, Stolz DB, Kiss LP, Monga SP, Holzman LB, Liu Y (2009) Wnt/beta-catenin signalling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol 20:1997–2008PubMedCrossRef

17.

Wang JJ, Zhang SX, Mott R et al (2006) Salutary effect of pigment epithelium-derived factor in diabetic nephropathy: evidence for antifibrogenic activities. Diabetes 55:1678–1685PubMedCrossRef

18.

Zhou T, Hu Y, Chen Y et al (2010) The pathogenic role of the canonical Wnt pathway in age-related macular degeneration. Invest Ophthalmol Vis Sci 51:4371–4379PubMedCrossRef

19.

Dunn SR, Qi Z, Bottinger EP, Breyer MD, Sharma K (2004) Utility of endogenous creatinine clearance as a measure of renal function in mice. Kidney Int 65:1959–1967PubMedCrossRef

20.

Gurley SB, Mach CL, Stegbauer J et al (2010) Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am J Physiol Renal Physiol 298:F788–F795PubMedCrossRef

21.

Schrijvers BF, de Vriese AS, Flyvbjerg A (2004) From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev 25:971–1010PubMedCrossRef

22.

Huang JS, Chuang LY, Guh JY, Huang YJ, Hsu MS (2007) Antioxidants attenuate high glucose-induced hypertrophic growth in renal tubular epithelial cells. Am J Physiol Renal Physiol 293:F1072–F1082PubMedCrossRef

23.

Calabrese V, Mancuso C, Sapienza M et al (2007) Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones 12:299–306PubMedCrossRef

24.

Furfaro AL, Menini S, Patriarca S et al (2005) HNE-dependent molecular damage in diabetic nephropathy and its possible prevention by N-acetyl-cysteine and oxerutin. Biofactors 24:291–298PubMedCrossRef

25.

Lin SL, Li B, Rao S et al (2010) Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci USA 107:4194–4199PubMedCrossRef

26.

Rane MJ, Song Y, Jin S et al (2010) Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy. Am J Physiol Renal Physiol 298:F49–F61PubMedCrossRef

27.

Ortiz-Munoz G, Lopez-Parra V, Lopez-Franco O et al (2010) Suppressors of cytokine signalling abrogate diabetic nephropathy. J Am Soc Nephrol 21:763–772PubMedCrossRef

28.

Okazaki Y, Yamasaki Y, Uchida HA et al (2007) Enhanced TGF-beta/Smad signalling in the early stage of diabetic nephropathy is independent of the AT1a receptor. Clin Exp Nephrol 11:77–87PubMedCrossRef

29.

Poli G, Schaur RJ, Siems WG, Leonarduzzi G (2008) 4-Hydroxynonenal: a membrane lipid oxidation product of medicinal interest. Med Res Rev 28:569–631PubMedCrossRef

30.

Zhou T, Zhou KK, Lee K et al (2010) The role of lipid peroxidation products and oxidative stress in activation of the canonical wingless-type MMTV integration site (WNT) pathway in a rat model of diabetic retinopathy. Diabetologia 54:459–468PubMedCrossRef

31.

Aslanidi G, Kroutov V, Philipsberg G et al (2007) Ectopic expression of Wnt10b decreases adiposity and improves glucose homeostasis in obese rats. Am J Physiol Endocrinol Metab 293:E726–E736PubMedCrossRef

32.

Vasudevan AR, Burns A, Fonseca VA (2006) The effectiveness of intensive glycemic control for the prevention of vascular complications in diabetes mellitus. Treat Endocrinol 5:273–286PubMedCrossRef

33.

Eastman DK, Bottenberg MM, Hegge KA, Ourth H, Kabadi U (2009) Intensive insulin therapy in critical care settings. Curr Clin Pharmacol 4:71–77PubMedCrossRef

34.

Hakim FA, Pflueger A (2010) Role of oxidative stress in diabetic kidney disease. Med Sci Monit 16:RA37–RA48PubMed

35.

Ha H, Hwang IA, Park JH, Lee HB (2008) Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract 82(Suppl 1):S42–S45PubMedCrossRef

36.

Wagener FA, Dekker D, Berden JH, Scharstuhl A, van der Vlag J (2009) The role of reactive oxygen species in apoptosis of the diabetic kidney. Apoptosis 14:1451–1458PubMedCrossRef

37.

Cohen CD, Lindenmeyer MT, Eichinger F et al (2008) Improved elucidation of biological processes linked to diabetic nephropathy by single probe-based microarray data analysis. PLoS One 3:e2937PubMedCrossRef

38.

Hsieh TJ, Chen R, Zhang SL et al (2006) Upregulation of osteopontin gene expression in diabetic rat proximal tubular cells revealed by microarray profiling. Kidney Int 69:1005–1015PubMedCrossRef

39.

Morrisey K, Steadman R, Williams JD, Phillips AO (1999) Renal proximal tubular cell fibronectin accumulation in response to glucose is polyol pathway dependent. Kidney Int 55:160–167PubMedCrossRef

40.

Liu Y (2009) New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 21:212–222PubMedCrossRef

41.

Chen CC, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783PubMedCrossRef

42.

Zhang B, Abreu JG, Zhou K et al (2010) Blocking the Wnt pathway, a unifying mechanism for an angiogenic inhibitor in the serine proteinase inhibitor family. Proc Natl Acad Sci USA 107:6900–6905PubMedCrossRef

43.

Ziyadeh FN, Hoffman BB, Han DC et al (2000) Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci USA 97:8015–8020PubMedCrossRef

44.

Guha M, Xu ZG, Tung D, Lanting L, Natarajan R (2007) Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J 21:3355–3368PubMedCrossRef

45.

Elmarakby AA, Sullivan JC (2011) Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther. doi:10.1111/j.1755-5922.2010.00218.x

46.

Surendran K, Schiavi S, Hruska KA (2005) Wnt-dependent beta-catenin signalling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis. J Am Soc Nephrol 16:2373–2384PubMedCrossRef

Title: Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy
Authors: T. Zhou
X. He
R. Cheng
B. Zhang
R. R. Zhang
Y. Chen
Y. Takahashi
A. R. Murray
K. Lee
G. Gao
J-x. Ma
Publication date: 01-01-2012
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 1/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2314-2

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

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

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Please log in to get access to this content

Other articles of this Issue 1/2012

Cellular characterisation of the GCKR P446L variant associated with type 2 diabetes risk

Insulin analogues and cancer risk: the emergence of second-generation studies

High cerebral insulin sensitivity is associated with loss of body fat during lifestyle intervention

Association studies of novel obesity-related gene variants with quantitative metabolic phenotypes in a population-based sample of 6,039 Danish individuals

High mobility group box 1 is a novel substrate of dipeptidyl peptidase-IV

Reversible severe deterioration of glycaemic control after withdrawal of metformin treatment

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

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

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page