Liver X receptor-α mediates cholesterol efflux in glomerular mesangial cells

Lipid-mediated injury plays an important role in the pathogenesis of many renal diseases including diabetic nephropathy. Liver X receptor-α (LXRα) 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 LXRα 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 LXRα, respectively. Tissue distribution studies showed that rabbit LXRα was expressed in the liver, spleen, and kidney. In situ hybridization and RT-PCR assays further indicated that LXRα mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli. To determine intrarenal regulation of LXRα, rabbits were treated with thiazolidinedione (TZD) peroxisome proliferator-activated receptor-γ (PPARγ) agonists, which have been previously shown to enhance LXRα expression via PPARγ and increase cholesterol efflux in macrophages. The results showed that glomerular LXRα expression was markedly induced by TZDs. In cultured rabbit mesangial cells, LXRα mRNA and protein were detected by RT-PCR and immunoblotting. Treatment of mesangial cells with a specific LXRα agonist, TO-901317, significantly increased basal and apolipoprotein AI-mediated cholesterol efflux and markedly enhanced the promoter activity of an LXRα target gene, ATP-binding cassette transporter A1 (ABCA1). In conclusion, LXRα is expressed in renal glomeruli and functionally present in mesangial cells where its activation mediates cholesterol efflux via ABCA1. These data suggest that LXRα may be a potential therapeutic target for treating lipid-related renal glomerular disease.