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Am J Physiol Renal Physiol (July 27, 2004). doi:10.1152/ajprenal.00123.2004
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Submitted on April 6, 2004
Accepted on June 30, 2004

Liver X Receptor alpha (LXR{alpha}) Mediates Cholesterol Efflux in Glomerular Mesangial Cells

Jing Wu1, Yahua Zhang1, Nanping Wang1, Linda Davis1, Guangrui Yang1, Xian Wang1, Yi Zhu1, Matthew D Breyer1, and Youfei Guan1*

1 Physiology and Pathophysiology, Peking University Health Science Center, Beijing, Beijing, China

* To whom correspondence should be addressed. E-mail: youfei.guan{at}vanderbilt.edu.

Lipid-mediated injury plays an important role in pathogenesis of many renal diseases including diabetic nephropathy. LXR{alpha} 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{alpha} in cholesterol metabolism in glomerular mesangial cells. A 1,561 bp of full-length rabbit LXR{alpha} cDNA was cloned. The deduced protein sequence exhibited 92.4% and 89.2% identity to human and mouse LXR{alpha}, respectively. Tissue distribution studies showed that rabbit LXR{alpha} was expressed in the liver, spleen and kidney. In situ hybridization and RT-PCR assays further indicated that LXR{alpha} mRNA was widely expressed in the kidney and present in every nephron segment including the glomeruli. To determine intrarenal regulation of LXR{alpha}, rabbits were treated with thiazolidinedione (TZD) PPAR{gamma} agonists which have been previously shown to enhance LXR{alpha} expression via PPAR{gamma} and increase cholesterol efflux in macrophages. The results show that glomerular LXR{alpha} expression is markedly induced by TZDs. In cultured rabbit mesangial cells, LXR{alpha} mRNA and protein were detected by RT-PCR and immunoblotting. Treatment of mesangial cells with a specific LXR{alpha} agonist TO901317 significantly increased basal and apoAI-mediated cholesterol efflux and markedly enhanced the promoter activity of an LXR{alpha} target gene, ATP binding cassette transporter A1 (ABCA1). In conclusion, LXR{alpha} is expressed in renal glomeruli and functionally present in mesangial cells where its activation mediates cholesterol efflux via ABCA1. These data suggest that LXR{alpha} may be a potential therapeutic target for treating lipid-related renal glomerular disease.




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