Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Abstract

The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts.water homeostasis | bile acid receptor T he farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, with the typical functional domains including the DNA binding domain and the ligand binding domain. Upon binding to its ligands, FXR forms a heterodimer with another nuclear receptor, retinoid X receptor, whereupon the receptor dimer binds to the FXR response element (FXRE) located in the promoter regions of FXR target genes, thereby regulating the transcription of these genes (1-3). The single FXR gene gives rise to two isoforms, designated as FXRα and FXRβ, as a result of alternative use of the promoters (4). In addition, each FXR isoform has two variants (FXRα1/FXRβ1 and FXRα2/ β2), depending on the presence or absence of an insert of four amino acids (MYTG) immediately adjacent to the DNA binding domain in the hinge domain (5). Because FXRβ constitutes a pseudogene in humans and primates, all recent studies focus on FXRα (6).FXR is highly expressed in the liver and intestine, where it functions as an intracellular sensor of bile acids and is required for the negative feedback regulation of bile acid biosynthesis and its enterohepatic cycle (7,8). Most recently FXR has been found to be involved in the regulation of adrenal and vascular function, as well as hepatic glucose and lipid metabolism, which suggests an important role for FXR in many tissues beyond the hepatointestinal system (9-12). Among most tissues tested, the kidney exhibits the highest expression levels (13). However, the role of FXR in the kidney remains largely unknown. It has been previously reported that FXR may negatively regulate sterol regulatory element-binding protei...

Disruption of prostaglandin E2 receptor EP4 impairs urinary concentration via decreasing aquaporin 2 in renal collecting ducts

“…To verify whether EP4 was regulated in renal CDs during the process of urinary concentration, mouse primary inner medullary collecting duct (IMCD) cells were cultured as described previously (18). Hyperosmotic challenge (700-900 mOsm/kg H 2 O) induced EP4 protein expression in IMCD cells (SI Appendix, Fig.…”

Role of Lipocalin-type prostaglandin D2 synthase (L-PGDS) and its metabolite, prostaglandin D2, in preterm birth

“…Typically, fFN is absent from cervicovaginal secretions from 24 weeks until near term; however, 3-4% of women undergoing routine screening at 24-26 weeks are positive, and are at substantially increased risk of preterm delivery [9]. However, it has been less informative for the determination of term or PTB due to the limited two week window of accuracy of the clinical test [10]. Therefore, a novel biomarker is needed which can provide more accurate time of delivery or any correlation between the levels of a particular analyte and prediction of PTB.…”

Essential roles of bile acid receptors FXR and TGR5 as metabolic regulators

“…FXR orchestrates urine volume in mice. FXR activation reduces urine volume and increases urine osmolality in animals through induction of apical aquaporin 2 (AQP2; Zhang et al 2014). In contrast, with a reduction in osmolality, there was an increased urine output in FXRnull mice, suggesting the ability of FXR to concentrate urine became attenuated in FXR-null mice.…”

“…A heterodimer is formed with retinoid X receptor (RXR) by FXR when binding is initiated by endogenous ligands, the binding with BAs initiates the RXR/FXR heterodimer binding to the FXR response element which is located in the promoter regions of FXR target genes. An abundant expression of FXR has been reported in the hepatic liver as well as adrenal glands, kidney, and intestinal tract (Forman et al 1995;Lee et al 2006;Modica et al 2008Modica et al , 2010Zhang et al 2014), where it functions as an intracellular sensor of BAs to control BA synthesis in the liver (Makishima et al 1999;Lu et al 2000;Chiang 2002;Li-Hawkins et al 2002;Wang et al 2002). Recent discoveries have demonstrated that FXR is responsible to regulate hepatic glucose production, lipid metabolism, liver regeneration, intestinal homeostasis, function of pancreatic β cells, and urine concentration in the kidney (Edwards et al 2002;Huang et al 2006;Jiang et al 2007;Popescu et al 2010;Renga et al 2010;Zhang et al 2004Zhang et al , 2006Zhang et al , 2014.…”