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) Mediates Cholesterol Efflux in Glomerular Mesangial Cells
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
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 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) PPAR
agonists which have been previously shown to enhance LXR expression via PPAR and increase cholesterol efflux in macrophages. The results show that glomerular LXR expression is 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 TO901317 significantly increased basal and apoAI-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.
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