High Density Lipoprotein (HDL) Reduces Renal Ischemia/ Reperfusion Injury CHRISTOPH THIEMERMANN,* NIMESH S.A. PATEL,* ESPEN O. KVALE,* GILLIAN W. COCKERILL, † PAUL A.J. BROWN, ‡ KEITH N. STEWART, § SALVATORE CUZZOCREA, ¶ DOMENICO BRITTI, # HELDER MOTA-FILIPE, @ and PRABAL K. CHATTERJEE* Departments of *Experimental Medicine & Nephrology and † Experimental Therapeutics, William Harvey Research Institute, Queen Mary – University of London, UK; Departments of ‡ Pathology and § Medicine & Therapeutics, University of Aberdeen, UK; ¶ Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy; # Department of Veterinary and Agricultural Science, University of Teramo, Italy; and @ Laboratory of Pharmacology, University of Lisbon, Portugal. Abstract. High-density lipoproteins (HDL) have been shown to reduce organ injury and mortality in animal models of shock via modulation of the expression of adhesion molecules and pro-inflammatory enzymes. As renal inflammation plays an important role in the development of ischemia/reperfusion (I/R) injury of the kidney, the aim of this study was to inves- tigate the ability of HDL to alleviate renal dysfunction and injury in a rat model of renal I/R. HDL (80 mg/kg, intravenous) was administered to male Wistar rats 30 min before bilateral renal ischemia for 45 min followed by reperfusion for up to 48 h. After 6-h reperfusion, HDL significantly reduced (1) renal and tubular dysfunction, (2) tubular and reperfusion- injury, and (3) histologic evidence of renal injury. HDL also improved renal function (after 24-h and 48-h reperfusion) and reduced histologic signs of renal injury (after 48-h reperfu- sion). Administration of HDL significantly reduced the num- bers of polymorphonuclear leukocytes (PMN) infiltrating into renal tissues during reperfusion, which was reflected by an attenuation of the increase in renal myeloperoxidase activity caused by I/R. Furthermore, HDL markedly reduced expres- sion of the adhesion molecules, intercellular adhesion mole- cule-1 (ICAM-1), and P-selectin during reperfusion. The in- crease in renal malondialdehyde levels caused by renal I/R was also significantly reduced by HDL, suggesting attenuation of lipid peroxidation subsequent to oxidative stress. These results demonstrate that HDL significantly reduces renal I/R injury and severity of ischemic acute renal failure. It is proposed that the mechanism of protection involves reduction of the expres- sion of adhesion molecules, resulting in reduction of PMN infiltration and oxidative stress. High-density lipoproteins (HDL) represent a broad group of mostly spheroidal plasma lipoproteins that exhibit considerable diversity in their size and apolipoprotein and lipid composition. HDL particles fall into the density range of 1.063 to 1.21 g/ml (1); as they are smaller than other lipoproteins, HDL can penetrate between endothelial cells more readily, allowing relatively high concentrations to accumulate in tissue fluids (2). The major apolipoprotein (apo) of almost all plasma HDL is apo A-I, which, in association with phospholipids and cho- lesterol, encloses a core of cholesteryl esters (1). Nascent (i.e., newly synthesized) HDL secreted by the liver and intestine contain no cholesteryl esters and are discoidal in shape (1). A negative association of plasma HDL concentration with the risk of developing atherosclerosis and coronary heart disease has been documented from numerous epidemiologic studies (3,4) and animal experiments (5,6), demonstrating that HDL have direct anti-atherogenic activity (7). The mechanisms by which HDL provides these cardioprotective actions are not clearly understood but may include a role for HDL in reverse transport of cholesterol from peripheral tissues to the liver, inhibition of the oxidation of low-density lipoproteins, or mod- ulation of vasodilatation and platelet activation mediated by changes in the production of prostacyclin (8,9). HDL can also activate endothelial nitric oxide synthase subsequent to its interaction with scavenger receptor-B1 (SR-B1) (10). Although HDL are involved in the removal of cholesterol from extra-hepatic tissues, this subset of lipoproteins has re- cently been reported to possess functions unrelated to their role in plasma cholesterol transport. Almost 10 yr ago, it was reported that in transgenic mice in which plasma levels of HDL were twofold higher, the increase in plasma levels of TNF- as well as mortality caused by bacterial lipopolysaccharide (LPS) were significantly reduced (11). We and others have subse- quently demonstrated that administration of HDL significantly reduces organ injury and levels of mortality in animal models Received April 26, 2002. Accepted April 10, 2003. Correspondence to Professor Christoph Thiemermann, Department of Exper- imental Medicine & Nephrology, William Harvey Research Institute, Queen Mary – University of London, Charterhouse Square, London, EC1M 6BQ, UK. Phone: 44-0-20-7882 6118; Fax: 44-0-20-7251 1685; E-mail: c.thiemermann@qmul.ac.uk 1046-6673/1407-1833 Journal of the American Society of Nephrology Copyright © 2003 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000075552.97794.8C J Am Soc Nephrol 14: 1833–1843, 2003