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Modelling diabetic nephropathy in mice

Nature Reviews Nephrology volume 14, pages 48–56 (2018)Cite this article

Subjects

Key Points

  • Animal models that faithfully recapitulate the clinical features of diabetic nephropathy (DN) are needed to help to define the pathogenesis, identify new drug targets, and test novel therapies

  • Substantial efforts have focused on developing models of DN in mice owing to their tractability for genetic manipulation and other advantages such as fecundity and low cost

  • The extent of kidney pathology in standard mouse models of diabetes is typically quite modest, resembling only the early stage of diabetic microalbuminuria in humans

  • Superimposing genetic stressors on standard diabetes platforms has resulted in more robust mouse models of DN that manifest high-grade albuminuria, nodular glomerulosclerosis, and hypertension

  • No current models of DN develop progressive loss of renal function leading to end-stage renal disease

  • Incorporating data from genomics and metabolomics studies into modelling efforts should enable the generation of mouse models that more closely mimic human DN and thus enhance translational research in the field

Abstract

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the developed world. Accordingly, an urgent need exists for new, curative treatments as well as for biomarkers to stratify risk of DN among individuals with diabetes mellitus. A barrier to progress in these areas has been a lack of animal models that faithfully replicate the main features of human DN. Such models could be used to define the pathogenesis, identify drug targets and test new therapies. Owing to their tractability for genetic manipulation, mice are widely used to model human diseases, including DN. Questions have been raised, however, about the general utility of mouse models in human drug discovery. Standard mouse models of diabetes typically manifest only modest kidney abnormalities, whereas accelerated models, induced by superimposing genetic stressors, recapitulate key features of human DN. Incorporation of systems biology approaches and emerging data from genomics and metabolomics studies should enable further model refinement. Here, we discuss the current status of mouse models for DN, their limitations and opportunities for improvement. We emphasize that future efforts should focus on generating robust models that reproduce the major clinical and molecular phenotypes of human DN.

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Figure 1: Sequential impact of diabetes platforms, genetic backgrounds and accelerators on albuminuria and kidney pathology in mouse models of diabetic nephropathy (DN).
Figure 2: Glomerular pathology in mice and humans with diabetic nephropathy.

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Acknowledgements

The authors' work in this area has been supported by grants from the NIH (including 5U01DK076136 and funding from the Diabetes Complications Consortium), and the Singapore National Medical Research Council (NMRC/OFLCG/001/2017).

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Authors and Affiliations

  1. Cardiovascular and Metabolic Disorders Signature Research Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore

    Kengo Azushima & Thomas M. Coffman

  2. Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3–9 Fukuura, Kanazawa-ku, 236–0004, Yokohama, Japan

    Kengo Azushima

  3. Division of Nephrology, Department of Medicine, Duke University, and Durham VA Health Care System, 2 Genome Court, Durham, 27710, North Carolina, USA

    Susan B. Gurley & Thomas M. Coffman

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Azushima, K., Gurley, S. & Coffman, T. Modelling diabetic nephropathy in mice. Nat Rev Nephrol 14, 48–56 (2018). https://doi.org/10.1038/nrneph.2017.142

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