Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy.
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 proposed 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.
Wendt
Thoralf
T
Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Tanji
Nozomu
N
Guo
Jiancheng
J
Hudson
Barry I
BI
Bierhaus
Angelika
A
Ramasamy
Ravichandran
R
Arnold
Bernd
B
Nawroth
Peter P
PP
Yan
Shi Fang
SF
D'Agati
Vivette
V
Schmidt
Ann Marie
AM
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*
D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic