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Liver X receptor- mediates cholesterol efflux in glomerular mesangial cells

¹Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100083, People's Republic of China; and ²Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37212

Submitted 6 April 2004 ; accepted in final form 30 June 2004

Lipid-mediated injury plays an important role in the pathogenesis of many renal diseases including diabetic nephropathy. Liver X receptor- (LXR) is an intracellular sterol sensor that regulates expression of genes controlling cholesterol absorption, excretion, catabolism, and cellular efflux. The present study was aimed at examining the role of LXR in cholesterol metabolism in glomerular mesangial cells. A 1,561-bp fragment of full-length rabbit LXR cDNA was cloned. The deduced protein sequence exhibited 92.4 and 89.2% identity to human and mouse LXR, respectively. Tissue distribution studies showed that rabbit LXR was expressed in the liver, spleen, and kidney. In situ hybridization and RT-PCR assays further indicated that LXR mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli. To determine intrarenal regulation of LXR, rabbits were treated with thiazolidinedione (TZD) peroxisome proliferator-activated receptor- (PPAR) agonists, which have been previously shown to enhance LXR expression via PPAR and increase cholesterol efflux in macrophages. The results showed that glomerular LXR expression was markedly induced by TZDs. In cultured rabbit mesangial cells, LXR mRNA and protein were detected by RT-PCR and immunoblotting. Treatment of mesangial cells with a specific LXR agonist, TO-901317, significantly increased basal and apolipoprotein AI-mediated cholesterol efflux and markedly enhanced the promoter activity of an LXR target gene, ATP-binding cassette transporter A1 (ABCA1). In conclusion, LXR is expressed in renal glomeruli and functionally present in mesangial cells where its activation mediates cholesterol efflux via ABCA1. These data suggest that LXR may be a potential therapeutic target for treating lipid-related renal glomerular disease.

glomeruli; ATP-binding cassette transporter A1

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