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J Am Soc Nephrol 14:1383-1395, 2003
© 2003 American Society of Nephrology

FRONTIERS IN NEPHROLOGY

Glucose, Glycation, and RAGE: Implications for Amplification of Cellular Dysfunction in Diabetic Nephropathy

Thoralf Wendt*, Nozomu Tanji*, Jiancheng Guo*, Barry I. Hudson*, Angelika Bierhaus{dagger}, Ravichandran Ramasamy*, Bernd Arnold{ddagger}, Peter P. Nawroth{dagger}, Shi Fang Yan*, Vivette D’Agati* and Ann Marie Schmidt*

*Departments of Surgery, Medicine, and Pathology, College of Physicians and Surgeons, Columbia University, New York, New York; {dagger}Department of Medicine I, University of Heidelberg, Germany; and {ddagger}Department of Molecular Immunology, Division of Tumor Immunology, German Cancer Research Center, Heidelberg, Germany.

Correspondence to Dr. Ann Marie Schmidt, Division of Surgical Science, Department of Surgery, College of Physicians & Surgeons, Columbia University, 630 West 168 Street, P&S 17-501, New York, New York 10032. Phone: 212-305-6406; Fax: 212-305-5337;

ABSTRACT. Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accumulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in diabetic tissues, upregulation and activation of RAGE magnifies cellular perturbation in tissues affected by hyperglycemia, such as the large blood vessels and the kidney. In the diabetic glomerulus, RAGE is expressed principally by glomerular visceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and structural alterations in the kidney, in the absence of alterations in blood glucose. Recent studies in homozygous RAGE null mice support a key role for RAGE in glomerular perturbation in diabetes. Importantly, beyond diabetes, studies in other settings of glomerulopathies support a critical RAGE-dependent pathway in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is propsed in glomerular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomerular injury in diabetes and other sclerosing glomerulopathies. E-mail: ams11@columbia.edu




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