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  • Review Article
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Diabetic nephropathy: a disorder of oxygen metabolism?

Nature Reviews Nephrology volume 6, pages 83–95 (2010)Cite this article

Abstract

Chronic hypoxia induces sequential abnormalities in oxygen metabolism (for example, oxidative stress, nitrosative stress, advanced glycation, carbonyl stress, endoplasmic reticulum stress) in the kidneys of individuals with diabetes. Identification of these abnormalities improves our understanding of therapeutic benefits that can be achieved with antihypertensive agents, the control of hyperglycemia and/or hyperinsulinemia and the dietary correction of obesity. Key to the body's defense against hypoxia is hypoxia-inducible factor, the activity of which is modulated by prolyl hydroxylases (PHDs)—oxygen sensors whose inhibition may prove therapeutic. Renal benefits of small-molecule PHD inhibitors have been documented in several animal models, including those of diabetic nephropathy. Three different PHD isoforms have been identified (PHD1, PHD2 and PHD3) and their respective roles have been delineated in knockout mouse studies. Unfortunately, none of the current inhibitors is specific for a distinct PHD isoform. Nonspecific inhibition of PHDs might induce adverse effects, such as those associated with PHD2 inhibition. Specific disruption of PHD1 induces hypoxic tolerance, without angiogenesis and erythrocytosis, through the reprogramming of basal oxygen metabolism and decreased generation of oxidative stress in hypoxic mitochondria. A specific PHD1 inhibitor might, therefore, offer a novel therapy for abnormal oxygen metabolism not only in the diabetic kidney, but also in other diseases for which hypoxia is a final, common pathway.

Key Points

  • Chronic hypoxia induces sequential abnormalities in oxygen metabolism in the diabetic kidney, leading to oxidative stress, nitrosative stress, advanced glycation, carbonyl stress and endoplasmic reticulum stress

  • Understanding the key features of abnormal oxygen metabolism improves the interpretation of the therapeutic benefits achieved by antihypertensive therapy, the control of hyperglycemia and/or hyperinsulinemia and the dietary correction of obesity

  • Activity of hypoxia-inducible factor—central to the defense against hypoxia—is modulated by prolyl hydroxylases (PHDs), which act as oxygen sensors

  • Three PHD isoforms have been identified and their respective roles have been elucidated, but none of the current PHD inhibitors exhibits absolute specificity for any subtype

  • Disruption of PHD1 induces hypoxic tolerance by reducing oxidative stress in hypoxic mitochondria, indicating that a specific PHD1 inhibitor could be an innovative treatment for abnormal oxygen metabolism in the diabetic kidney

  • Treatment of chronic hypoxia might apply to other chronic diseases that share a final common pathway, including a wide variety of kidney disorders, ischemic heart disease, and stroke

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Figure 1: Causes of hypoxia in the diabetic kidney.
Figure 2
Figure 3: Interplay between hemodynamic or metabolic abnormalities and impaired oxygen metabolism in the diabetic kidney.
Figure 4: The HIF–PHD pathway.
Figure 5: Predicted binding modes of the PHD inhibitors to human PHD2.
Figure 6: Respective role of each PHD isoform in response to hypoxia.
Figure 7: Mechanisms of PHD inhibition, increased oxygen supply, and decreased oxygen demand (hypoxia tolerance).

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Acknowledgements

We thank Dr. Guo-Hua Fong for critically reviewing the manuscript, Drs. Masaomi Nangaku and Kotaro Takeda for helpful discussion, Dr. Noriaki Hirayama for kindly providing a representative picture of docking simulation (human PHD2 and PHD inhibitors), and Dr. Masashi Okamura for help with the preparation of figures.

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  1. Center for Translational and Advanced Research, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai, 980-8575, Miyagi, Japan

    Toshio Miyata

  2. Service de Nephrologie, Universite Catholique de Louvain Medical School, 10 Avenue Hippocrate, B-1200, Brussels, Belgium

    Charles van Ypersele de Strihou

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Miyata, T., van Ypersele de Strihou, C. Diabetic nephropathy: a disorder of oxygen metabolism?. Nat Rev Nephrol 6, 83–95 (2010). https://doi.org/10.1038/nrneph.2009.211

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