Differential effects of advanced glycation end-products on renal tubular cell inflammation

The authors recently showed that advanced glycation end-products (AGE) in the form of glycated albumin (GA) upregulated renal tubular expression of interleukin (IL)-8 and soluble intercellular adhesion molecule-1 (sICAM-1), but not other important cytokines known to mediate diabetic nephropathy. This implies that other molecules such as the carbonyl intermediates of AGE or other modified protein lysine-albumin may participate in diabetic tubular injury.

Human proximal tubular epithelial cells (PTEC) were growth-arrested and exposed to methylglyoxal (MG), MG-bovine serum albumin (BSA)-AGE, carboxymethyllysine (CML)-BSA, AGE-BSA or BSA with or without prior addition of rosiglitazone that was previously shown to attenuate the pro-inflammatory effect of GA alone.

MG-BSA-AGE and AGE-BSA upregulated tubular expression of connective tissue growth factor (CTGF), transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF), whereas CML-BSA stimulated expression of IL-6, CCL-2, CTGF, TGF-β and VEGF. These AGE compounds also activated nuclear factor (NF)-κB and their effects were attenuated by pre-incubation with anti-RAGE antibody. MG and BSA did not affect the expression of any of these molecules. Rosiglitazone did not affect the in vitro biological effects of MG, MG-BSA-AGE, AGE-BSA or CML-BSA on PTEC.

AGE exhibit differential inflammatory and fibrotic effects on PTEC via RAGE activation and NF-κB signal transduction. Rosiglitazone had no effect on these responses. Further investigations on compounds that nullify the downstream effects of these AGE are warranted.