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RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic
Thoralf M Wendt1, Nozomu Tanji, Jiancheng Guo
1Department of Pathology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Abstract:
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.
Insights
Diabetic nephropathy involves kidney damage, driven by receptor for advanced glycation endproducts (RAGE) activation. Blocking RAGE in diabetic mice reduced kidney disease markers and improved renal function.
Area of Science:
- Nephrology
- Diabetology
- Molecular Biology
Background:
- Diabetic nephropathy is a major complication of diabetes.
- Key pathological changes include glomerular and podocyte damage, and mesangial matrix accumulation.
- Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor-beta (TGF-beta) are implicated.
Purpose of the Study:
- To investigate the role of the receptor for advanced glycation endproducts (RAGE) in diabetic nephropathy.
- To determine if RAGE blockade or deficiency impacts disease progression and related molecular pathways.
Main Methods:
- Utilized genetically diabetic db/db mice and RAGE-null mice.
- Administered soluble RAGE (sRAGE) to diabetic mice.
- Assessed kidney function, albuminuria, glomerulosclerosis, and glomerular VEGF and inflammatory cell infiltration.
Main Results:
- RAGE expression was upregulated in podocytes of diabetic mice, correlating with VEGF levels and inflammatory cell recruitment.
- sRAGE treatment attenuated albuminuria, glomerulosclerosis, and improved renal function in diabetic mice.
- RAGE-deficient diabetic mice showed significantly reduced mesangial matrix expansion and glomerular basement membrane thickening.
Conclusions:
- RAGE activation in the diabetic glomerulus promotes VEGF expression and inflammatory cell infiltration.
- These RAGE-mediated events contribute to mesangial activation and TGF-beta production, driving albuminuria and glomerulosclerosis.
- Targeting RAGE may offer a therapeutic strategy for diabetic nephropathy.