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RAGE and the pathogenesis of chronic kidney disease

Abstract

The multiligand receptor of the immunoglobulin superfamily, receptor for advanced glycation endproducts (RAGE), is a signal transduction receptor that binds advanced glycation endproducts, certain members of the S100/calgranulin family of proteins, high mobility group box 1 (HMGB1), advanced oxidation protein products, and amyloid (β-sheet fibrils). Initial studies investigating the role of RAGE in renal dysfunction focused on diabetes. However, RAGE also has roles in the pathogenesis of renal disorders that are not associated with diabetes, such as obesity-related glomerulopathy, doxorubicin-induced nephropathy, hypertensive nephropathy, lupus nephritis, renal amyloidosis, and ischemic renal injuries. Experiments that have employed transgenic mouse models, pharmacological blockade of RAGE, or genetic deletion or modification of RAGE indicate that modulation of RAGE expression or function affects the functional and pathological properties of these nephropathies. Accumulating evidence links RAGE to the pathogenesis of nephropathies, indicating that antagonism of RAGE might be a strategy for the treatment of chronic kidney disease.

Key Points

  • The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor and a member of the immunoglobulin superfamily of cell surface molecules

  • RAGE ligands include advanced glycation endproducts, advanced oxidation protein products, certain members of the S100/calgranulin family, HMGB1, and certain forms of amyloid (β-sheet fibrils)

  • RAGE is normally expressed at low levels by podocytes, glomerular endothelial cells, and other cells of the kidney; RAGE expression is increased in both animal and human nephropathies

  • Pharmacological antagonism or genetic deletion of RAGE is highly protective against nephropathy induced by diabetes or doxorubicin

  • Studies in patients and in animal models implicate RAGE in the pathogenesis of nephropathies that are not associated with diabetes, such as lupus nephritis, obesity-related glomerulopathy, and hypertensive nephropathy

  • RAGE may be involved in varying stages of nephropathies, for example, in the early initiation stages by mediating podocyte stress, and in later stages, by amplifying inflammatory pathways

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Figure 1: Mechanisms by which RAGE induces glomerular stress.
Figure 2: Known forms of soluble RAGE.
Figure 3: Glomerular CCL2 may be involved in damage and/or repair mechanisms associated with inflammation.

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Acknowledgements

The authors gratefully acknowledge funding from the US Public Health Service and the Juvenile Diabetes Research Foundation for the work discussed in this Review. The authors thank Ms Latoya Woods, Division of Surgical Science, Department of Surgery, Columbia University, College of Physicians & Surgeons, NY, USA, for her expert assistance in the preparation of this manuscript.

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D'Agati, V., Schmidt, A. RAGE and the pathogenesis of chronic kidney disease. Nat Rev Nephrol 6, 352–360 (2010). https://doi.org/10.1038/nrneph.2010.54

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