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Title: Liver X receptor activation downregulates organic anion transporter 1 (OAT1) in the renal proximal tubule
Authors: Suticha Kittayaruksakul
Sunhapas Soodvilai
Nithi Asavapanumas
Chatchai Muanprasat
Varanuj Chatsudthipong
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Mar-2012
Citation: American Journal of Physiology - Renal Physiology. Vol.302, No.5 (2012)
Abstract: Liver X receptors (LXRs) play an important role in the regulation of cholesterol by regulating several transporters. In this study, we investigated the role of LXRs in the regulation of human organic anion transporter 1 (hOAT1), a major transporter localized in the basolateral membrane of the renal proximal tubule. Exposure of renal S2 cells expressing hOAT1 to LXR agonists (TO901317 and GW3965) and their endogenous ligand [22(R)-hydroxycholesterol] led to the inhibition of hOAT1-mediated [ 14 C]PAH uptake. This inhibition was abolished by coincubation of the above agonists with 22(S)-hydroxycholesterol, an LXR antagonist. Moreover, it was found that the effect of LXR agonists was not mediated by changes in intracellular cholesterol levels. Interestingly, the inhibitory effect of LXRs was enhanced in the presence of 9-cis retinoic acid, a retinoic X receptor agonist. Kinetic analysis revealed that LXR activation decreased the maximum rate of PAH transport (J max ) but had no effect on the affinity of the transporter (K t ). This result correlated well with data from Western blot analysis, which showed the decrease in hOAT1 expression following LXR activation. Similarly, TO901317 inhibited [ 14 C]PAH uptake by the renal cortical slices as well as decreasing mOAT1 protein expression in mouse kidney. Our findings indicated for the first time that hOAT1 was downregulated by LXR activation in the renal proximal tubule. © 2012 the American Physiological Society.
ISSN: 15221466
Appears in Collections:Scopus 2011-2015

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