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Advanced glycation end products and diabetic nephropathy: a comparative study using diabetic and normal rats with methylglyoxal-induced glycation

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Abstract

Hyperglycemia-related advanced glycation end product (AGE) formation is a key mechanism in diabetic nephropathy. Since methylglyoxal (MG) is a potent AGE precursor, we aimed to assess the role of MG-related AGE formation in the progression of renal damages. A comparative study between Wistar (W, normal) and Goto-Kakizaki (GK, nonobese type 2 diabetic) rats was performed at 6 and 14 months old and after 14 weeks of MG administration to 6-month-old rats. Diabetic rats showed progressive structural, biochemical, and functional alterations, including AGE, albuminuria, and tissue hypoxia, which were partially mimicked by MG administration to young GK rats. Aged Wistar rats had an impairment of some parameters, whereas MG administration caused a phenotype similar to young GK rats, including oxidative stress, impaired apoptotic and angiogenic markers, and structural lesions. MG accumulation specifically impaired several of the renal disease markers progressively observed in diabetic rats, and thus, it contributes to the progression of diabetic nephropathy.

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References

  1. Advani A, Gilbert R (2012) The endothelium in diabetic nephropathy. Semin Nephrol 32(2):199–207

    Article  CAS  PubMed  Google Scholar 

  2. American Diabetes Association (2012) Summary of revisions for the 2012—clinical practice recommendations. Diabetes Care 35(Supplement 1):S3. doi:10.2337/dc12-s003

    Google Scholar 

  3. Bento CF, Fernandes R, Matafome P, Sena C, Seiça R, Pereira P (2010) Methylglyoxal-induced imbalance in the ratio of vascular endothelial growth factor to angiopoietin 2 secreted by retinal pigment epithelial cells leads to endothelial dysfunction. Exp Physiol 95(9):955–970

    CAS  PubMed  Google Scholar 

  4. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  5. Chang F, Lai T, Chiang C, Chen Y, Wu M, Chu T, Wu K, Lin S (2013) Angiopoietin-2 is associated with microalbuminuria and microinflammation in chronic kidney disease. PlosOne 8:e54668

    Article  CAS  Google Scholar 

  6. Cooper ME, Vranes D, Youssef S, Stacker S, Cox A, Rizkalla B, Casley D, Bach L, Kelly D, Gilbert R (1999) Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 48:2229–2239

    Article  CAS  PubMed  Google Scholar 

  7. Eleftheriadis T, Antoniadi G, Pissas G, Liakopoulos V, Stefanidis I (2013) The renal endothelium in diabetic nephropathy. Ren Fail 35(4):592–599

    Article  CAS  PubMed  Google Scholar 

  8. Fedorov L, Schmittwolf C, Amann K, Thomas WH, Müller AM, Schubert H, Domen J, Kneitz B (2006) Renal failure causes early death of bcl-2 deficient mice. Mech Ageing Dev 127(7):600–609

    Article  CAS  PubMed  Google Scholar 

  9. Foster RR (2009) The importance of cellular VEGF bioactivity in the development of glomerular disease. Nephron Exp Nephrol 113:e8–e15

    Article  CAS  PubMed  Google Scholar 

  10. Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605

    Article  CAS  PubMed  Google Scholar 

  11. Harcourt B, Sourris K, Coughlan M et al (2011) Targeted reduction of advanced glycation improves renal function in obesity. Kidney Int 80(2):190–198

    Article  CAS  PubMed  Google Scholar 

  12. Huebschmann AG, Regensteiner JG, Vlassara H, Reusch JE (2006) Diabetes and advanced glycoxidation end products. Diabetes Care 29(6):1420–1432

    Article  CAS  PubMed  Google Scholar 

  13. Jakus V, Rietbrock N (2004) Advanced glycation end products and the progress of diabetic vascular complications. Physiol Res 53:131–142

    CAS  PubMed  Google Scholar 

  14. Kumagai T, Nangaku M, Kojima I, Nagai R, Ingelfinger J, Miyata T, Fujita T, Inagi R (2009) Glyoxalase I overexpression ameliorates renal ischemic-reperfusion injury in rats. Am J Physiol Renal Physiol 296:F912–F921

    Article  CAS  PubMed  Google Scholar 

  15. Lindermen RD, Goldman R (1986) Anatomic and physiologic age changes in the kidney. Exp Gerontol 21(4–5):379–406

    Google Scholar 

  16. Matafome P, Santos-Silva D, Crisóstomo J, Rodrigues T, Rodrigues L, Sena C, Pereira P, Seiça R (2012) Methylglyoxal causes structural and functional alterations in adipose tissue independently of obesity. Arch Physiol Biochem 118(2):58–68

    Article  CAS  PubMed  Google Scholar 

  17. Matafome P, Sena C, Seiça R (2013) Methylglyoxal. Obes Diabetes 43(3):472–484

    CAS  Google Scholar 

  18. Reiniger N, Lau K, McCalla D et al (2010) Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes 59:2043–2054

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Rosca MG, Mustata TG, Kinter MT, Ozdemir A, Kern T, Szweda L, Brownlee M, Monnier V, Weiss M (2005) Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol 289:F420–F430

    Article  CAS  PubMed  Google Scholar 

  20. Ruiz-Torres MP, Bosch RJ, O’Valle F et al (1998) Age-related increase in expression of TGF-beta1 in the rat kidney: relationship to morphologic changes. J Am Soc Nephrol 9(5):782–791

    CAS  PubMed  Google Scholar 

  21. Satchell SC, Tooke JE (2008) What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia 51:714–725

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Sena CM, Matafome P, Crisóstomo J, Rodrigues L, Fernandes R, Pereira P, Seiça R (2012) Methylglyoxal promotes oxidative stress and endothelial dysfunction. Pharmacol Res 65(5):497–506

    Article  CAS  PubMed  Google Scholar 

  23. Sena C, Matafome P, Louro T, Nunes E, Fernandes R, Seiça R (2011) Metformin restores endothelial function in aorta of diabetic rats. Br J Pharmacol 63(2):424–437

    Article  Google Scholar 

  24. Shroff R, Price K, Kolatsi-Joannou M et al (2013) Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis. PlosOne 8:e56273

    Article  CAS  Google Scholar 

  25. Vlassara H, Uribarri J (2004) Glycoxidation and diabetic complications: modern lessons and a warning? Rev End Metab Dis 5:181–188

    Article  CAS  Google Scholar 

  26. Wolf G, Ziyadeh FN (1999) Molecular mechanisms of diabetic renal hypertrophy. Kidney Int 56:393–405

    Article  CAS  PubMed  Google Scholar 

  27. Xu Y, Chen X (2006) Glyoxalase II, a detoxifying enzyme of glycolysis byproduct methylglyoxal and a target of p63 and p73, is a pro-survival factor of the p53 family. J Biol Chem 281(36):26702–26713

    Article  CAS  PubMed  Google Scholar 

  28. Yamagishi S, Inagaki Y, Okamoto T, Amano S, Koga K, Takeuhi M (2003) Advanced glycation end products inhibit de novo protein synthesis and induce TGF-beta overexpression in proximal tubular cells. Kidney Int 63(2):464–473

    Article  CAS  PubMed  Google Scholar 

  29. Yan S, Ramasamy R, Naka Y, Schmidt AM (2003) Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ Res 93(12):1159–1169

    Article  CAS  PubMed  Google Scholar 

  30. Yao D, Taguchi T, Matsumura T, Pestell P, Edelstein D, Giardino I, Suske G, Rabbani N, Thornalley P, Sarthy V, Hammes HP, Brownlee M (2007) High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem 282(42):31038–31045

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Mário Simões from the Laboratory of Physiology, Faculty of Medicine of Coimbra, for his technical support. We also thank Ilda Simões, from Serviço de Patologia Clínica from the University Hospital of Coimbra for technical support. We thank the Portuguese Foundation for Science and Technology (FCT; projects PTDC/SAU-OSM/67498/2006 and Pest-C/SAU/UI3282/2011) and the Faculty of Medicine, University of Coimbra, for the funding received.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Laboratory of Physiology–IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Lisa Rodrigues, Paulo Matafome, Joana Crisóstomo, Daniela Santos-Silva, Cristina Sena & Raquel Seiça

  2. Center of Ophthalmology and Visual Sciences–IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal

    Paulo Matafome & Paulo Pereira

  3. Faculty of Medicine, Pole III of University of Coimbra, Subunit 1, 1st Floor, Azinhaga de Santa Comba, Celas, 3000-354, Coimbra, Portugal

    Paulo Matafome

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  1. Lisa Rodrigues
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  2. Paulo Matafome
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  4. Daniela Santos-Silva
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Correspondence to Paulo Matafome.

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Lisa Rodrigues and Paulo Matafome are coauthors of the present study.

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Rodrigues, L., Matafome, P., Crisóstomo, J. et al. Advanced glycation end products and diabetic nephropathy: a comparative study using diabetic and normal rats with methylglyoxal-induced glycation. J Physiol Biochem 70, 173–184 (2014). https://doi.org/10.1007/s13105-013-0291-2

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  • DOI: https://doi.org/10.1007/s13105-013-0291-2

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