RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy

被引:562
作者
Wendt, TM
Tanji, N
Guo, JC
Kislinger, TR
Qu, W
Lu, Y
Bucciarelli, LG
Rong, LL
Moser, B
Markowitz, GS
Stein, G
Bierhaus, A
Liliensiek, B
Arnold, B
Nawroth, PP
Stern, DM
D'Agati, VD
Schmidt, AM
机构
[1] Columbia Univ Coll Phys & Surg, Dept Surg, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[3] Columbia Univ Coll Phys & Surg, Dept Physiol, New York, NY 10032 USA
[4] Columbia Univ Coll Phys & Surg, Dept Cellular Biophys, New York, NY 10032 USA
[5] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA
[6] Univ Jena, Dept Internal Med 4, D-6900 Jena, Germany
[7] Heidelberg Univ, Dept Med 1, Heidelberg, Germany
[8] German Canc Res Ctr, Dept Mol Immunol, Div Tumor Immunol, D-6900 Heidelberg, Germany
关键词
D O I
10.1016/S0002-9440(10)63909-0
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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-beta (TGF-beta), 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-beta production; processes which converge to cause albuminuria and glomerulosclerosis.
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页码:1123 / 1137
页数:15
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