Enhanced RAGE-mediated NFκB stimulation in inflamed hemodialysis patients

Advanced glycation end-products (AGEs), a group of carbohydrate-derived compounds formed by non-enzymatic glycation and oxidation, are markedly elevated in end-stage renal disease (ESRD) and may be related to both inflammation and oxidative stress. The cellular effects of AGE are largely mediated by their interaction with specific surface receptors, such as RAGE. Measurements of biomarkers of inflammation and oxidative stress were conducted in 7 hemodialysis (HD) patients (5 males) with persistent high-grade inflammation (C-reactive protein [CRP] > 10 mg/L) and 11 HD-patients (6 males) with low-grade inflammation (CRP < 10 mg/L) for at least 6 months. Measured biomarkers for inflammation included hs-CRP, interleukin (IL)-6, white blood cells, neutrophils, S-albumin, peroxisome proliferator-activated receptors (PPAR α, β, γ) and nuclear factor κB (NFκB) activity. Markers for oxidative stress were advanced oxidation products (AOPP), myeloperoxidase (MPO)-activity, pentosidine and carboxymethyl lysine (CML). In addition, the effect of increasing doses of CML-modified human serum albumin on NFκB activity was tested in mononuclear cells isolated from each patient. As expected, HD-patients with high-grade inflammation had significantly elevated levels of IL-6 (median 9.2 pg/mL versus 2.5 pg/mL; p < 0.01), MPO-activity (134.5 ± 14.6 ΔOD630/(min mg protein) versus 80.5 ± 12.9 ΔOD630/(min mg protein); p < 0.05), PPAR-γ (0.65 ± 0.01 OD655 versus 0.56 ± 0.01 OD655; p < 0.01), and AOPP (269 ± 54 μM versus 163 ± 15 μM; p < 0.05) compared with low-grade inflamed patients. Significant associations were demonstrated between hs-CRP and NFκB (ρ = 0.58; p < 0.05), AOPP (ρ = 0.49; p < 0.05) and PPAR-γ (ρ = 0.62; p < 0.05), respectively. In the patient group with high-grade inflammation, stimulation of mononuclear cells with CML-modified human serum albumin caused a rapid dose-dependent rise (p < 0.0001) in NFκB activity that could be completely blocked by an anti-RAGE antibody. Inflammation and oxidative stress biomarkers are interrelated in ESRD. Inflammatory cell signal pathways, such as NFκB, are activated by CML-modification of proteins via RAGE.