Serum Amyloid A in Uremic HDL Promotes Inflammation : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

Weichhart, Thomas*; Kopecky, Chantal*; Kubicek, Markus†; Haidinger, Michael*; Döller, Dominik*; Katholnig, Karl*; Suarna, Cacang‡; Eller, Philipp§; Tölle, Markus‖; Gerner, Christopher¶; Zlabinger, Gerhard J.**; van der Giet, Markus‖; Hörl, Walter H.*; Stocker, Roland‡; Säemann, Marcus D.*

*Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria;

†Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria;

‡Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, Sydney Medical School, University of Sydney, Camperdown, Australia;

§Department of Internal Medicine I, Graz Medical University, Graz, Austria;

‖Charité—Universitätsmedizin Berlin, Campus Benjamin Franklin, Med. Klinik mit Schwerpunkt Nephrologie, Berlin, Germany;

¶Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; and

**Institute of Immunology, Medical University of Vienna, Vienna, Austria

Correspondence: Dr. Thomas Weichhart or Dr. Marcus D. Säemann, Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria. Email: [email protected] or [email protected]

Received July 11, 2011

Accepted November 30, 2011

Abstract

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.