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  • Review Article
  • Published:

Diabetic nephropathy—emerging epigenetic mechanisms

Nature Reviews Nephrology volume 10, pages 517–530 (2014)Cite this article

Subjects

Key Points

  • Diabetic conditions induce inflammation, fibrosis and hypertrophy in renal cells through various cytokines and growth factors such as transforming growth factor β1, angiotensin II and platelet-derived growth factor

  • The engagement of cytokines and growth factors with their receptors triggers signal transduction cascades that result in the activation of transcription factors to increase expression of inflammatory and fibrotic genes

  • These signalling mechanisms affect epigenetic states—such as DNA methylation and chromatin histone modifications—to augment the expression of profibrotic and inflammatory genes, as well as noncoding RNAs

  • Noncoding RNAs that are induced by diabetic conditions can also promote the expression of pathological genes via various post-transcriptional and post-translational mechanisms

  • These epigenetic mechanisms and noncoding RNAs can lead to persistently open chromatin structures at pathological genes and sustained gene expression, which can also be a mechanism for 'metabolic memory'

  • Key epigenetic regulators, microRNAs and long noncoding RNAs could serve as new therapeutic targets for diabetic nephropathy

Abstract

Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure. The condition can also lead to accelerated cardiovascular disease and macrovascular complications. Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease. Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor β1 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN. These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs. In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN.

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Figure 1: Emerging molecular mechanisms of diabetic nephropathy.
Figure 2: Regulation of gene transcription in DN mediated by histone lysine modifications.

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Acknowledgements

The authors gratefully acknowledge funding from the National Institutes of Health (NIDDK and NHLBI), the Juvenile Diabetes Research Foundation and the American Diabetes Association.

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  1. Department of Diabetes, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, 91010, CA, USA

    Mitsuo Kato & Rama Natarajan

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  1. Mitsuo Kato
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Both authors researched the data for the article, discussed its content, wrote the manuscript and edited the article before submission.

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Kato, M., Natarajan, R. Diabetic nephropathy—emerging epigenetic mechanisms. Nat Rev Nephrol 10, 517–530 (2014). https://doi.org/10.1038/nrneph.2014.116

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