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Clinical Reviews
Medwave 2017 Ene-feb;16(1):6839 doi: 10.5867/medwave.2017.01.6839
Pathophysiology of diabetic nephropathy: a literature review
Carlos Eduardo Meza Letelier, Camilo Alfredo San Martín Ojeda, José Javier Ruiz Provoste, Cristobal Jesus Frugone Zaror
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Key Words: diabetic nephropathy, microvascular complications, chronic renal disease physiopathology

Abstract

Chronic kidney disease is a common complication of diabetes. Its importance lies in its high prevalence and future projection. It is associated with high health costs and global cardiovascular deterioration as well. The development of this disease pathophysiology is being studied and it is known that a series of complex molecular pathways determining a microvascular disease are involved. This review addresses the known pathways in the development of diabetic nephropathy aiming to improve the understanding of potential therapeutic targets that could be developed in the future.


 

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Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

La enfermedad renal crónica es una complicación frecuente en la diabetes mellitus. Su importancia radica en la alta prevalencia y la proyección a futuro que ésta tiene. Se asocia a altos gastos en salud y además a deterioro cardiovascular global. La fisiopatología del desarrollo de esta enfermedad está siendo estudiada y se sabe que en ella participan una serie de vías moleculares complejas que determinan una enfermedad microvascular. En esta revisión se intenta abordar las vías conocidas en el desarrollo de nefropatía diabética, con el fin de comprender mejor posibles blancos terapéuticos que se podrían desarrollar.

Autores: Carlos Eduardo Meza Letelier[1], Camilo Alfredo San Martín Ojeda[1], José Javier Ruiz Provoste[1], Cristobal Jesus Frugone Zaror[1]

Affiliation:
[1] Facultad de Medicina, Universidad Católica del Maule, Talca, Región del Maule, Chile

E-mail: c.meza.letelier@gmail.com

Author address:
[1] Calle Cuatro y Medio Norte B 3415
Talca
Región del Maule
Chile

Citation: Meza Letelier CE, San Martín Ojeda CA, Ruiz Provoste JJ, Frugone Zaror CJ. Pathophysiology of diabetic nephropathy: a literature review. Medwave 2017 Ene-feb;16(1):6839 doi: 10.5867/medwave.2017.01.6839

Submission date: 28/10/2016

Acceptance date: 12/12/2016

Publication date: 12/1/2017

Origin: no solicitado

Type of review: con revisión por tres pares revisores externos, a doble ciego

PubMed record

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  1. Organizacion Mundial de la Salud. Informe mundial sobre la diabetes. Ginebra: WHO;2016. | Link |
  2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442. | PubMed |
  3. Organizacion mundial de la salud. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Ginebra. WHO;1999. | Link |
  4. Gobierno de Chile Ministerio de Salud. [Acquired immunodeficiency syndrome]. Rev Chilena Infectol. 2010 Jun;27(3):239-76. | CrossRef | PubMed |
  5. Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010 Jun 26;375(9733):2215-22. | CrossRef | PubMed |
  6. Gobierno de Chile, Ministerio de Salud. Encuesta nacional de salud ENS Chile 2009-2010. Chile: Minsal, 2010
  7. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. | PubMed |
  8. Mount DB, Pollak MR, editors. Molecular and genetic basis of renal disease. Elsevier; 2008. | Link |
  9. Association AD. Nephropathy in diabetes. Diabetes Care. 2004 Jan;27(suppl 1):s79-s83. | CrossRef |
  10. Koeppen B, Stanton B. El sistema renal en: Fisiologia. Elsevier Sanders; 2009: 557-577.
  11. Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: The role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004 Dec;25(6):971-1010. | CrossRef | PubMed |
  12. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003 May;14(5):1358-73. | PubMed |
  13. Cortes P, Méndez M, Riser BL, Guérin CJ, Rodríguez-Barbero A, Hassett C, et al. F-actin fiber distribution in glomerular cells: structural and functional implications. Kidney Int. 2000 Dec;58(6):2452-61. | PubMed |
  14. Fliser D, Wagner KK, Loos A, Tsikas D, Haller H. Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Am Soc Nephrol. 2005 Apr;16(4):1135-40. | PubMed |
  15. Najafian B, Alpers CE, Fogo AB. Pathology of human diabetic nephropathy. Contrib Nephrol. 2011;170:36-47. | CrossRef | PubMed |
  16. Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010 Apr;21(4):556-63. | CrossRef | PubMed |
  17. Mora-Fernandez C, Macías Heras M, Martínez-Castellao A, Gorriz Teruel J, De Alvaro Moreno F, Navarro-Gonzalez F. Fisiopatologia de la nefropatía diabética. Nefrología. 2008;1(1):28-38. | Link |
  18. Tan A, Forbes J, Cooper M. AGE, RAGE, and ROS in diabetic nephropathy. Seminars in nephrology. 2007 Apr 10;27(2):130–43. | CrossRef | PubMed |
  19. Hernández JC, Licea Puig ME, Hernándes García P, Abraham Marcel EA, Yanes Quesada M. Estrés oxidativo y diabetes mellitus. Rev Mex Patol Clin. 2011;58(1):4-15. | Link |
  20. Pawan Krishan VA. Diabetic nephropathy: aggressive involvement of oxidative stress. J Pharm Educ Res. 2011;2(1):35-41.
  21. Hodgkinson AD, Søndergaard KL, Yang B, Cross DF, Millward BA, Demaine AG. Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy. Kidney Int. 2001 Jul;60(1):211-8. | PubMed |
  22. Sung JK, Koh JH, Lee MY, Kim BH, Nam SM, Kim JH, et al. Aldose reductase inhibitor ameliorates renal vascular endothelial growth factor expression in streptozotocin-induced diabetic rats. Yonsei Med J. 2010 May;51(3):385-91. | CrossRef | PubMed |
  23. Xie P, Sun L, Oates PJ, Srivastava SK, Kanwar YS. Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis. Am J Physiol Renal Physiol. 2010 Jun;298(6):F1393-404. | CrossRef | PubMed |
  24. Inoguchi T, Sonta T, Tsubouchi H, Etoh T, Kakimoto M, Sonoda N, et al. Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S227-32. | PubMed |
  25. Li J, Gobe G. Protein kinase C activation and its role in kidney disease. Nephrology (Carlton). 2006 Oct;11(5):428-34. | PubMed |
  26. Lee MR, Duan W, Tan SL. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin Ther Targets. 2008 May;12(5):535-52. | CrossRef | PubMed |
  27. Rodríguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson RJ. Role of immunocompetent cells in nonimmune renal diseases. Kidney Int. 2001 May;59(5):1626-40. | CrossRef | PubMed |
  28. Yadav A, Vallabu S, Arora S, Tandon P, Slahan D, Teichberg S, et al. ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol. 2010 Aug;299(2):C488-96. | CrossRef | PubMed |
  29. Kumar V, Abbas AK, Aster JC. The endocrine pancreas En: Robbins & Cotran. Pathologic Basis of Disease. Elsevier Sanders; 2014: 1105-1117.
  30. Tuttle KR. Linking metabolism and immunology: diabetic nephropathy is an inflammatory disease. J Am Soc Nephrol. 2005 Jun;16(6):1537-8. | PubMed |
  31. Navarro JF, Mora C. Role of inflammation in diabetic complications. Nephrol Dial Transplant. 2005 Dec;20(12):2601-4. | PubMed |
  32. Navarro-González JF, Mora-Fernández C. The role of inflammatory Cytokines in diabetic Nephropathy. Journal of the American Society of Nephrology. 2008. Mar;19(3):433-42. | CrossRef | PubMed |
  33. Vilcek J. the cytokines: an overview, in the cytokine handbook, London, Elsevier Sanders, 2003:3-18.
  34. DiPetrillo K, Gesek FA. Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats. Am J Nephrol. 2004 May-Jun;24(3):352-9. | PubMed |
  35. Dai SM, Matsuno H, Nakamura H, Nishioka K, Yudoh K. Interleukin-18 enhances monocyte tumor necrosis factor alpha and interleukin-1beta production induced by direct contact with T lymphocytes: implications in rheumatoid arthritis. Arthritis Rheum. 2004 Feb;50(2):432-43. | PubMed |
  36. Navarro-González J, Mora-Fernández C, de Fuentes M, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy: Abstract: Nature reviews Nephrology. Nature Reviews Nephrology. 2011 May 3;7(6):327–40. | CrossRef |
  37. Fermin I, Milagro Y. Epigenética en obesidad y diabetes tipo 2: papel de la nutrición, limitaciones y futuras aplicaciones. Rev Chil Endocrinol Diabetes. 2013;6(3):108-114. | Link |
  38. Conserva F, Gesualdo L, Papale M. A Systems Biology Overview on Human Diabetic Nephropathy: From Genetic Susceptibility to Post-Transcriptional and Post-Translational Modifications. J Diabetes Res. 2016;2016:7934504. | CrossRef | PubMed |
  39. Gudsnuk KM, Champagne FA. Epigenetic effects of early developmental experiences. Clin Perinatol. 2011 Dec;38(4):703-17. | CrossRef | PubMed |
  40. Najafian B, Alpers C, Fogo A. Pathology of human diabetic nephropathy. Contrib Nephrol. 2011;170:36-47. | CrossRef | PubMed |
Organizacion Mundial de la Salud. Informe mundial sobre la diabetes. Ginebra: WHO;2016. | Link |

Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006 Nov;3(11):e442. | PubMed |

Organizacion mundial de la salud. Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Ginebra. WHO;1999. | Link |

Gobierno de Chile Ministerio de Salud. [Acquired immunodeficiency syndrome]. Rev Chilena Infectol. 2010 Jun;27(3):239-76. | CrossRef | PubMed |

Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, Ingelsson E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010 Jun 26;375(9733):2215-22. | CrossRef | PubMed |

Gobierno de Chile, Ministerio de Salud. Encuesta nacional de salud ENS Chile 2009-2010. Chile: Minsal, 2010

Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005 Jun;54(6):1615-25. | PubMed |

Mount DB, Pollak MR, editors. Molecular and genetic basis of renal disease. Elsevier; 2008. | Link |

Association AD. Nephropathy in diabetes. Diabetes Care. 2004 Jan;27(suppl 1):s79-s83. | CrossRef |

Koeppen B, Stanton B. El sistema renal en: Fisiologia. Elsevier Sanders; 2009: 557-577.

Schrijvers BF, De Vriese AS, Flyvbjerg A. From hyperglycemia to diabetic kidney disease: The role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr Rev. 2004 Dec;25(6):971-1010. | CrossRef | PubMed |

Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003 May;14(5):1358-73. | PubMed |

Cortes P, Méndez M, Riser BL, Guérin CJ, Rodríguez-Barbero A, Hassett C, et al. F-actin fiber distribution in glomerular cells: structural and functional implications. Kidney Int. 2000 Dec;58(6):2452-61. | PubMed |

Fliser D, Wagner KK, Loos A, Tsikas D, Haller H. Chronic angiotensin II receptor blockade reduces (intra)renal vascular resistance in patients with type 2 diabetes. J Am Soc Nephrol. 2005 Apr;16(4):1135-40. | PubMed |

Najafian B, Alpers CE, Fogo AB. Pathology of human diabetic nephropathy. Contrib Nephrol. 2011;170:36-47. | CrossRef | PubMed |

Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010 Apr;21(4):556-63. | CrossRef | PubMed |

Mora-Fernandez C, Macías Heras M, Martínez-Castellao A, Gorriz Teruel J, De Alvaro Moreno F, Navarro-Gonzalez F. Fisiopatologia de la nefropatía diabética. Nefrología. 2008;1(1):28-38. | Link |

Tan A, Forbes J, Cooper M. AGE, RAGE, and ROS in diabetic nephropathy. Seminars in nephrology. 2007 Apr 10;27(2):130–43. | CrossRef | PubMed |

Hernández JC, Licea Puig ME, Hernándes García P, Abraham Marcel EA, Yanes Quesada M. Estrés oxidativo y diabetes mellitus. Rev Mex Patol Clin. 2011;58(1):4-15. | Link |

Pawan Krishan VA. Diabetic nephropathy: aggressive involvement of oxidative stress. J Pharm Educ Res. 2011;2(1):35-41.

Hodgkinson AD, Søndergaard KL, Yang B, Cross DF, Millward BA, Demaine AG. Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy. Kidney Int. 2001 Jul;60(1):211-8. | PubMed |

Sung JK, Koh JH, Lee MY, Kim BH, Nam SM, Kim JH, et al. Aldose reductase inhibitor ameliorates renal vascular endothelial growth factor expression in streptozotocin-induced diabetic rats. Yonsei Med J. 2010 May;51(3):385-91. | CrossRef | PubMed |

Xie P, Sun L, Oates PJ, Srivastava SK, Kanwar YS. Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis. Am J Physiol Renal Physiol. 2010 Jun;298(6):F1393-404. | CrossRef | PubMed |

Inoguchi T, Sonta T, Tsubouchi H, Etoh T, Kakimoto M, Sonoda N, et al. Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S227-32. | PubMed |

Li J, Gobe G. Protein kinase C activation and its role in kidney disease. Nephrology (Carlton). 2006 Oct;11(5):428-34. | PubMed |

Lee MR, Duan W, Tan SL. Protein kinase C isozymes as potential therapeutic targets in immune disorders. Expert Opin Ther Targets. 2008 May;12(5):535-52. | CrossRef | PubMed |

Rodríguez-Iturbe B, Pons H, Herrera-Acosta J, Johnson RJ. Role of immunocompetent cells in nonimmune renal diseases. Kidney Int. 2001 May;59(5):1626-40. | CrossRef | PubMed |

Yadav A, Vallabu S, Arora S, Tandon P, Slahan D, Teichberg S, et al. ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol. 2010 Aug;299(2):C488-96. | CrossRef | PubMed |

Kumar V, Abbas AK, Aster JC. The endocrine pancreas En: Robbins & Cotran. Pathologic Basis of Disease. Elsevier Sanders; 2014: 1105-1117.

Tuttle KR. Linking metabolism and immunology: diabetic nephropathy is an inflammatory disease. J Am Soc Nephrol. 2005 Jun;16(6):1537-8. | PubMed |

Navarro JF, Mora C. Role of inflammation in diabetic complications. Nephrol Dial Transplant. 2005 Dec;20(12):2601-4. | PubMed |

Navarro-González JF, Mora-Fernández C. The role of inflammatory Cytokines in diabetic Nephropathy. Journal of the American Society of Nephrology. 2008. Mar;19(3):433-42. | CrossRef | PubMed |

Vilcek J. the cytokines: an overview, in the cytokine handbook, London, Elsevier Sanders, 2003:3-18.

DiPetrillo K, Gesek FA. Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats. Am J Nephrol. 2004 May-Jun;24(3):352-9. | PubMed |

Dai SM, Matsuno H, Nakamura H, Nishioka K, Yudoh K. Interleukin-18 enhances monocyte tumor necrosis factor alpha and interleukin-1beta production induced by direct contact with T lymphocytes: implications in rheumatoid arthritis. Arthritis Rheum. 2004 Feb;50(2):432-43. | PubMed |

Navarro-González J, Mora-Fernández C, de Fuentes M, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy: Abstract: Nature reviews Nephrology. Nature Reviews Nephrology. 2011 May 3;7(6):327–40. | CrossRef |

Fermin I, Milagro Y. Epigenética en obesidad y diabetes tipo 2: papel de la nutrición, limitaciones y futuras aplicaciones. Rev Chil Endocrinol Diabetes. 2013;6(3):108-114. | Link |

Conserva F, Gesualdo L, Papale M. A Systems Biology Overview on Human Diabetic Nephropathy: From Genetic Susceptibility to Post-Transcriptional and Post-Translational Modifications. J Diabetes Res. 2016;2016:7934504. | CrossRef | PubMed |

Gudsnuk KM, Champagne FA. Epigenetic effects of early developmental experiences. Clin Perinatol. 2011 Dec;38(4):703-17. | CrossRef | PubMed |

Najafian B, Alpers C, Fogo A. Pathology of human diabetic nephropathy. Contrib Nephrol. 2011;170:36-47. | CrossRef | PubMed |