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  • Review Article
  • Published:

Endothelial dysfunction as a potential contributor in diabetic nephropathy

Nature Reviews Nephrology volume 7, pages 36–44 (2011)Cite this article

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Abstract

The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30–40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin–angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.

Key Points

  • Not all patients with diabetes mellitus develop advanced diabetic nephropathy

  • Similar to some patients with diabetes, animal models of the disease usually develop only early manifestations of diabetic nephropathy (such as mesangial expansion) and nephropathy (such as pericyte ghost formation)

  • Severe endothelial dysfunction might be required for the development of advanced diabetic nephropathy in humans as well as animals

  • Not all patients with diabetic nephropathy benefit from treatment with inhibitors of the renin–angiotensin system (RAS)

  • The effects of RAS inhibitors on diabetic nephropathy and retinopathy might differ

  • Failure of RAS inhibitors to prevent the progression of diabetic nephropathy might be accounted for by endothelial dysfunction

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Figure 1: Factors that contribute to the development of endothelial dysfunction in patients with diabetes.
Figure 2: Development of acellular capillaries in the retina of diabetic eNOS-knockout mice.
Figure 3: Potential mechanisms by which endothelial nitric oxide deficiency causes advanced renal injury in diabetes.
Figure 4: Proposed mechanism by which aldosterone causes renal injury and hypertension in diabetes independent of angiotensin II.

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Change history

  • 09 November 2010

    In the version of this article initially published online, there was a mistake in Figure 2. The errors have been corrected in all electronic versions of the text.

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Authors and Affiliations

  1. Division of Renal Disease and Hypertension, University of Colorado Denver, 12700 East 19th Avenue, Aurora, 80045, CO, USA

    Takahiko Nakagawa, Katsuyuki Tanabe, Richard J. Johnson & Tomoki Kosugi

  2. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1600 SW Archer Road, Gainesville, 32610, FL, USA

    Byron P. Croker

  3. Department of Pharmacology, University of Florida, 1600 SW Archer Road, Gainesville, 32610, FL, USA

    Maria B. Grant

  4. Department of Ophthalmology, University of Florida, 1600 SW Archer Road, Gainesville, 32610, FL, USA

    Qiuhong Li

Authors
  1. Takahiko Nakagawa
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  2. Katsuyuki Tanabe
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  3. Byron P. Croker
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  4. Richard J. Johnson
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  5. Maria B. Grant
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  6. Tomoki Kosugi
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Contributions

T. Nakagawa, K. Tanabe, B. P. Croker, T. Kosugi and Q. Li contributed equally to researching data for this article. T. Nakagawa and M. B. Grant contributed equally to discussions of the content. T. Nakagawa wrote the article, and T. Nakagawa and R. J. Johnson contributed equally to reviewing/editing the manuscript before submission.

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Correspondence to Takahiko Nakagawa.

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Nakagawa, T., Tanabe, K., Croker, B. et al. Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat Rev Nephrol 7, 36–44 (2011). https://doi.org/10.1038/nrneph.2010.152

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