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Perspectives in Diabetes

From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease

Podocyte Injury Comes of Age in Diabetic Nephropathy

  1. Gunter Wolf1,
  2. Sheldon Chen2 and
  3. Fuad N. Ziyadeh2
  1. 1Department of Internal Medicine (Klinik für Innere Medizin III), University Hospital, Jena, Germany
  2. 2Department of Medicine, Renal-Electrolyte and Hypertension Division, Penn Center for the Molecular Studies of Kidney Diseases, University of Pennsylvania, Philadelphia, Pennsylvania
  1. Address correspondence and reprint requests to Fuad N. Ziyadeh, MD, Professor of Medicine, Renal-Electrolyte and Hypertension Division, University of Pennsylvania, 700 Clinical Research Building, 415 Curie Blvd., Philadelphia, PA 19104-4218. E-mail: ziyadeh{at}mail.med.upenn.edu
Diabetes 2005 Jun; 54(6): 1626-1634. https://doi.org/10.2337/diabetes.54.6.1626
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Podocyte Injury Comes of Age in Diabetic Nephropathy

Abstract

Nephropathy is a major complication of diabetes. Alterations of mesangial cells have traditionally been the focus of research in deciphering molecular mechanisms of diabetic nephropathy. Injury of podocytes, if recognized at all, has been considered a late consequence caused by increasing proteinuria rather than an event inciting diabetic nephropathy. However, recent biopsy studies in humans have provided evidence that podocytes are functionally and structurally injured very early in the natural history of diabetic nephropathy. The diabetic milieu, represented by hyperglycemia, nonenzymatically glycated proteins, and mechanical stress associated with hypertension, causes downregulation of nephrin, an important protein of the slit diaphragm with antiapoptotic signaling properties. The loss of nephrin leads to foot process effacement of podocytes and increased proteinuria. A key mediator of nephrin suppression is angiotensin II (ANG II), which can activate other cytokine pathways such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) systems. TGF-β1 causes an increase in mesangial matrix deposition and glomerular basement membrane (GBM) thickening and may promote podocyte apoptosis or detachment. As a result, the denuded GBM adheres to Bowman’s capsule, initiating the development of glomerulosclerosis. VEGF is both produced by and acts upon the podocyte in an autocrine manner to modulate podocyte function, including the synthesis of GBM components. Through its effects on podocyte biology, glomerular hemodynamics, and capillary endothelial permeability, VEGF likely plays an important role in diabetic albuminuria. The mainstays of therapy, glycemic control and inhibition of ANG II, are key measures to prevent early podocyte injury and the subsequent development of diabetic nephropathy.

  • AGE, advanced glycation end product
  • ANG II, angiotensin II
  • CD2AP, CD2-associated protein
  • GBM, glomerular basement membrane
  • HSPG, heparan sulfate proteoglycans
  • RAGE, receptor for AGE
  • ROS, reactive oxygen species
  • STZ, streptozotocin
  • TGF-β, transforming growth factor-β
  • VEGF, vascular endothelial growth factor

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted January 19, 2005.
    • Received December 7, 2004.
  • DIABETES
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June 2005, 54(6)
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From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease
Gunter Wolf, Sheldon Chen, Fuad N. Ziyadeh
Diabetes Jun 2005, 54 (6) 1626-1634; DOI: 10.2337/diabetes.54.6.1626

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From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease
Gunter Wolf, Sheldon Chen, Fuad N. Ziyadeh
Diabetes Jun 2005, 54 (6) 1626-1634; DOI: 10.2337/diabetes.54.6.1626
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  • Article
    • Abstract
    • PODOCYTE BIOLOGY
    • PODOCYTOPATHY IN HUMAN DIABETIC KIDNEY DISEASE
    • PODOCYTE DYSFUNCTION IN EXPERIMENTAL DIABETES
    • PODOCYTE APOPTOSIS AND/OR DETACHMENT IN HUMANS AND ANIMAL MODELS
    • ROLE OF ANG II IN NEPHRIN EXPRESSION AND PODOCYTE INJURY
    • ROLE OF HEPARAN SULFATE PROTEOGLYCANS
    • ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR
    • ROLE OF TGF-β1
    • CONCLUSIONS
    • Acknowledgments
    • Footnotes
    • REFERENCES
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