Glucose, Glycation, and RAGE: Implications for Amplification of Cellular Dysfunction in Diabetic Nephropathy THORALF WENDT,* NOZOMU TANJI,* JIANCHENG GUO,* BARRY I. HUDSON,* ANGELIKA BIERHAUS, † RAVICHANDRAN RAMASAMY,* BERND ARNOLD, ‡ PETER P. NAWROTH, † 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; † Department of Medicine I, University of Heidelberg, Germany; and ‡ Department of Molecular Immunology, Division of Tumor Immunology, German Cancer Research Center, Heidelberg, Germany. Abstract. Receptor for advanced glycation endproducts (RAGE) is a multi-ligand member of the immunoglobulin superfamily of cell surface molecules. Driven by rapid accu- mulation and expression of key ligands such as advanced glycation endproducts (AGE) and S100/calgranulins in dia- betic 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 vis- ceral epithelial cells (podocytes). Blockade of RAGE in the hyperglycemic db/db mouse suppresses functional and struc- tural 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 path- way in podocytes linked to albuminuria, mesangial expansion, and glomerular sclerosis. A new paradigm is propsed in glo- merular injury, and it is suggested that blockade of the RAGE axis may provide a novel means to prevent irreparable glomer- ular injury in diabetes and other sclerosing glomerulopathies. The “Problem” of Glucose Irrespective of the underlying mechanisms, elevated levels of blood glucose ignite a vicious cycle of metabolic distur- bances within the intracellular and extracellular environment that, if left unchecked, lead to a broad array of complications in macrovessel and microvessel structures. A particular target in this setting is the kidney. Epidemiologic studies demonstrate that diabetes is a leading cause worldwide of end-stage renal failure requiring renal replacement therapy (1). A number of pathways are activated in the hyperglycemic milieu, such as the aldose reductase pathway, activation of protein kinase C, especially the  isoform, and the generation of advanced glycation endproducts (AGE). Work from Dr. Michael Brown- lee’s laboratory indicates that there is fundamental crosstalk among these pathways, as evidenced by the demonstration that normalization of mitochondrial superoxide dismutase, blocked each of these three pathways in cultured bovine aortic endo- thelial cells subjected to hyperglycemia-driven generation of reactive oxygen species (2). In vivo, the roles of each of multiple pathways implicated in the pathogenesis of diabetic nephropathy have been rigorously tested experimentally. Examples of these include activation of aldose reductase and protein kinase C, particularly the  iso- form. Importantly, however, roles for other pathways, such as activation of the family of mitogen-activated protein kinases (MAP kinases) and the transcription factor nuclear factor-B (NF-B) have been linked to the pathogenesis of hyperglyce- mia-mediated stress (3). Two examples of mediators of hyper- glycemic stress will be addressed here. First, roles for aldose reductase (AR) have been implicated in the adverse cellular response to high levels of glucose (4 –5). Multiple studies indicate that expression and activity of aldose reductase is increased in experimental models and human tissues in diabetes, including the diabetic kidney (6 –7). Phar- macologic inhibition of AR has implicated AR in the devel- opment of diabetes-associated nephropathy; for example, ad- ministration of the inhibitor epalrestat to streptozotocin- induced diabetic rats prevented the development of renal hypofunction and mesangial expansion without affecting levels Correspondence to Dr. Ann Marie Schmidt, Division of Surgical Science, Department of Surgery, College of Physicians & Surgeons, Columbia Univer- sity , 630 West 168 Street, P&S 17-501, New York, New York 10032. Phone: 212-305-6406; Fax: 212-305-5337; E-mail: ams11@columbia.edu 1046-6673/1405-1383 Journal of the American Society of Nephrology Copyright © 2003 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000065100.17349.CA J Am Soc Nephrol 14: 1383–1395, 2003