Abstract
Inorganic phosphate (Pi) homeostasis is regulated by intestinal absorption via type II sodium-dependent co-transporter (Npt2b) and by renal reabsorption via Npt2a and Npt2c. Although we previously reported that vitamin A-deficient (VAD) rats had increased urine Pi excretion through the decreased renal expression of Npt2a and Npt2c, the effect of vitamin A on the intestinal Npt2b expression remains unclear. In this study, we investigated the effects of treatment with all-trans retinoic acid (ATRA), a metabolite of vitamin A, on the Pi absorption and the Npt2b expression in the intestine of VAD rats, as well as and the underlying molecular mechanisms. In VAD rats, the intestinal Pi uptake activity and the expression of Npt2b were increased, but were reduced by the administration of ATRA. The transcriptional activity of reporter plasmid containing the promoter region of the rat Npt2b gene was reduced by ATRA in NIH3T3 cells overexpressing retinoic acid receptor (RAR) and retinoid X receptor (RXR). On the other hand, CCAAT/enhancer-binding proteins (C/EBP) induced transcriptional activity of the Npt2b gene. Knockdown of the C/EBP gene and a mutation analysis of the C/EBP responsible element in the Npt2b gene promoter indicated that C/EBP plays a pivotal role in the regulation of Npt2b gene transcriptional activity by ATRA. EMSA revealed that the RAR/RXR complex inhibits binding of C/EBP to Npt2b gene promoter. Together, these results suggest that ATRA may reduce the intestinal Pi uptake by preventing C/EBP activation of the intestinal Npt2b gene.
Highlights
Inorganic phosphate (Pi) homeostasis in mammals is strictly controlled through the balance of intestinal absorption and renal excretion/reabsorption [1,2]
In vitamin A-deficient (VAD) rats, the plasma parathyroid hormone (PTH) level was not affected by all-trans retinoic acid (ATRA), whereas the plasma 1,25(OH)2D3 and fibroblast growth factor 23 (FGF23) levels were significantly reduced by ATRA (Table 1)
The Na+-dependent Pi uptake activity — but not the Na+independent Pi uptake activity — in renal brush border membrane vesicles (BBMVs) was markedly decreased in VAD rats, which was significantly increased by ATRA treatment (Figure 1A)
Summary
Inorganic phosphate (Pi) homeostasis in mammals is strictly controlled through the balance of intestinal absorption and renal excretion/reabsorption [1,2]. The regulation of the intestinal Pi absorption mediated by Npt2b is a possible therapeutic target to control hyperphosphatemia in CKD [16]. The physiological actions of ATRA, a metabolite of vitamin A, are mediated by specific nuclear receptors, including retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These receptors are members of the steroid/thyroid hormone nuclear receptor superfamily, which act as ligand-dependent transcriptional factors. We previously reported that the renal expression of Npt2a and Npt2c is decreased in vitamin A-deficient (VAD) rats, and that the transcriptional activity of human Npt2a and Npt2c genes is up-regulated by ATRA and its receptors [4]. We characterized the Npt2b gene promoter with regard to transcriptional regulation through RAR/RXR and C/EBP
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