Liver X receptor-activating ligands modulate renal and intestinal sodium–phosphate transporters

• Published in: Kidney international Vol. 80; no. 5; pp. 535 - 544
• Main Authors: Caldas, Yupanqui A., Giral, Hector, Cortázar, Michael A., Sutherland, Eileen, Okamura, Kayo, Blaine, Judith, Sorribas, Victor, Koepsell, Hermann, Levi, Moshe
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.09.2011; Nature Publishing Group; Elsevier Limited
• Subjects: Animals; arteriosclerosis; Biological and medical sciences; Biological Transport; chronic kidney disease; Homeostasis; Humans; hyperphosphatemia; Intestines - metabolism; Kidney - metabolism; Kidneys; Ligands; Liver X Receptors; Medical sciences; Mice; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - metabolism; phosphate uptake; Phosphates - metabolism; Phosphates - urine; Renal failure; Sodium-Phosphate Cotransporter Proteins - metabolism; Urinary system involvement in other diseases. Miscellaneous; vascular calcification; arteriosclerosis; chronic kidney disease; phosphate uptake; hyperphosphatemia; vascular calcification; Hydroelectrolytic balance disorder; Nephrology; Nuclear receptor; Ligand; Inorganic element; Kidney; Urology; Sodium phosphate; Blood vessel; Kidney disease; Urinary system disease; Digestive system; Gut; Phosphorus; Chronic kidney disease; Uptake; Metabolic disorder; Urinary system; Renal failure; Calcification; Hyperphosphatemia; Liver X receptor; Circulatory system
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2011.159

Cholesterol is pumped out of the cells in different tissues, including the vasculature, intestine, liver, and kidney, by the ATP-binding cassette transporters. Ligands that activate the liver X receptor (LXR) modulate this efflux. Here we determined the effects of LXR agonists on the regulation of phosphate transporters. Phosphate homeostasis is regulated by the coordinated action of the intestinal and renal sodium–phosphate (NaPi) transporters, and the loss of this regulation causes hyperphosphatemia. Mice treated with DMHCA or TO901317, two LXR agonists that prevent atherosclerosis in ApoE or LDLR knockout mice, significantly decreased the activity of intestinal and kidney proximal tubular brush border membrane sodium gradient-dependent phosphate uptake, decreased serum phosphate, and increased urine phosphate excretion. The effects of DMHCA were due to a significant decrease in the abundance of the intestinal and renal NaPi transport proteins. The same effect was also found in opossum kidney cells in culture after treatment with either agonist. There was increased nuclear expression of the endogenous LXR receptor, a reduction in NaPi4 protein abundance (the main type II NaPi transporter in the opossum cells), and a reduction in NaPi co-transport activity. Thus, LXR agonists modulate intestinal and renal NaPi transporters and, in turn, serum phosphate levels.