RAGE Drives the Development of Glomerulosclerosis and Implicates Podocyte Activation in the Pathogenesis of Diabetic Nephropathy

• Published in: The American journal of pathology Vol. 162; no. 4; pp. 1123 - 1137
• Main Authors: Wendt, Thoralf M., Tanji, Nozomu, Guo, Jiancheng, Kislinger, Thomas R., Qu, Wu, Lu, Yan, Bucciarelli, Loredana G., Rong, Ling Ling, Moser, Bernhard, Markowitz, Glen S., Stein, Gunther, Bierhaus, Angelika, Liliensiek, Birgit, Arnold, Bernd, Nawroth, Peter P., Stern, David M., D'Agati, Vivette D., Schmidt, Ann Marie
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.04.2003; ASIP; American Society for Investigative Pathology
• Subjects: Albuminuria - pathology; Animals; Associated diseases and complications; Biological and medical sciences; Cell Differentiation; Cells, Cultured; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - pathology; Disease Models, Animal; Disease Progression; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Glomerulonephritis; Glycation End Products, Advanced - metabolism; Kidney Cortex - pathology; Male; Medical sciences; Mice; Mice, Mutant Strains; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Receptor for Advanced Glycation End Products; Receptors, Immunologic - physiology; Regular; Urothelium - pathology; Endocrinopathy; Kidney disease; Immunohistochemistry; Urinary system disease; Biochemical analysis; Pathogenesis; Diabetes mellitus; Rodentia; Podocyte; Pathology; Vertebrata; Experimental disease; Mammalia; Nephropathy; Mouse; Animal; Sclerotic kidney; Molecular biology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/S0002-9440(10)63909-0

Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-β (TGF-β), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGEs) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-β production; processes which converge to cause albuminuria and glomerulosclerosis.