Serum Amyloid A in Uremic HDL Promotes Inflammation

• Published in: Journal of the American Society of Nephrology 2012-05, Vol.23 (5), p.934-947
• Main Authors: WEICHHART, Thomas, KOPECKY, Chantal, ZLABINGER, Gerhard J, DER GIET, Markus Van, HÖRL, Walter H, STOCKER, Roland, SÄEMANN, Marcus D, KUBICEK, Markus, HAIDINGER, Michael, DÖLLER, Dominik, KATHOLNIG, Karl, SUARNA, Cacang, ELLER, Philipp, TÖLLE, Markus, GERNER, Christopher
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological and medical sciences; Clinical Research; Female; Humans; Inflammation - etiology; Iron - metabolism; Kidney Failure, Chronic - blood; Lipoproteins, HDL - physiology; Male; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oxidation-Reduction; Proteomics; Pulmonary Surfactant-Associated Protein B - blood; Renal failure; Serum Amyloid A Protein - physiology; Uremia - blood
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2011070668

Uremia impairs the atheroprotective properties of HDL, but the mechanisms underlying why this occurs are unknown. Here, we observed that HDL isolated from healthy individuals inhibited the production of inflammatory cytokines by peripheral monocytes stimulated with a Toll-like receptor 2 agonist. In contrast, HDL isolated from the majority of patients with ESRD did not show this anti-inflammatory property; many HDL samples even promoted the production of inflammatory cytokines. To investigate this difference, we used shotgun proteomics to identify 49 HDL-associated proteins in a uremia-specific pattern. Proteins enriched in HDL from patients with ESRD (ESRD-HDL) included surfactant protein B (SP-B), apolipoprotein C-II, serum amyloid A (SAA), and α-1-microglobulin/bikunin precursor. In addition, we detected some ESRD-enriched proteins in earlier stages of CKD. We did not detect a difference in oxidation status between HDL isolated from uremic and healthy patients. Regarding function of these uremia-specific proteins, only SAA mimicked ESRD-HDL by promoting inflammatory cytokine production. Furthermore, SAA levels in ESRD-HDL inversely correlated with its anti-inflammatory potency. In conclusion, HDL has anti-inflammatory activities that are defective in uremic patients as a result of specific changes in its molecular composition. These data suggest a potential link between the high levels of inflammation and cardiovascular mortality in uremia.