NF-κB Modulates Aquaporin-2 Transcription in Renal Collecting Duct Principal Cells

Hasler, Udo; Leroy, Valérie; Jeon, Un Sil; Bouley, Richard; Dimitrov, Milen; Kim, Jeong Ah; Brown, Dennis; Kwon, Hyug Moo; Martin, Pierre‐Yves; Féraille, Eric

doi:10.1074/jbc.m708350200

Cited by 70 publications

(87 citation statements)

References 49 publications

(48 reference statements)

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“…The collecting ducts play a determining role in final urine volume, depending on AQP2 expression and localization. Collecting duct AQP2 abundance is largely regulated by the AVP/V2 receptor system and to a less extent by prostaglandins and the transcription factors nuclear factor kappa B and tonicity-responsive enhancer binding protein (39). The present study has uncovered a unique mechanism by which AQP2 is regulated by FXR, independent of AVP and other known factors.…”

Section: Discussionmentioning

confidence: 79%

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

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 79%

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

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…We have also demonstrated that NF-B activation directly inhibits aquaporin 2 (AQP2) gene transcription via binding of NF-B to the AQP2 promoter. 53 Activation of NF-B may then participate in the downregulated expression of AQP2 mRNA observed in response to aldosterone in CD cells. 54 In conclusion, activation of NF-B by aldosterone in renal tubule epithelial cells may constitute a negative feedback mechanism that decreases aldosterone-dependent sodium transport, modulates water reabsorption, and/or participates in chronic tubulointerstitial inflammation.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Activates NF-κB in the Collecting Duct

Leroy

Seigneux²,

Agassiz³

et al. 2009

Journal of the American Society of Nephrology

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Besides its classical effects on salt homeostasis in renal epithelial cells, aldosterone promotes inflammation and fibrosis and modulates cell proliferation. The proinflammatory transcription factor NF-B has been implicated in cell proliferation, apoptosis, and regulation of transepithelial sodium transport. The effect of aldosterone on the NF-B pathway in principal cells of the cortical collecting duct, a major physiologic target of aldosterone, is unknown. Here, in both cultured cells and freshly isolated rat cortical collecting duct, aldosterone activated the canonical NF-B signaling pathway, leading to increased expression of several NF-B-targeted genes (IB␣, plasminogen activator inhibitor 1, monocyte chemoattractant protein 1, IL-1␤, and IL-6). Small interfering RNA-mediated knockdown of the serum and glucocorticoid-inducible kinase SGK1, a gene induced early in the response to aldosterone, but not pharmacologic inhibition of extracellular signal-regulated kinase and p38 kinase, attenuated aldosterone-induced NF-B activation. Pharmacologic antagonism or knockdown of the mineralocorticoid receptor prevented aldosterone-induced NF-B activity. In addition, activation of the glucocorticoid receptor inhibited the transactivation of NF-B by aldosterone. In agreement with these in vitro findings, spironolactone prevented NF-B-induced transcriptional activation observed in cortical collecting ducts of salt-restricted rats. In summary, aldosterone activates the canonical NF-B pathway in principal cells of the cortical collecting duct by activating the mineralocorticoid receptor and by inducing SGK1.

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“…Similar to classical NFκB stimulation, hypertonic stress increases NFκB activity and NFκB activation is at least party responsible for AQP2 transcriptional repression on the onset of hypertonic stress. 7 This effect, however, is transient 7,8 and appears to be mediated by p65 release and binding of p50 and p52 to both κB sites.…”

mentioning

confidence: 99%

“…Deletion of either site increases AQP2 transcriptional activity under baseline conditions, indicating that they act as transcriptional repressors. 7 NFκB activation by cytokines or lipopolysaccharides (LPS) decreases AQP2 transcription. Similar to classical NFκB stimulation, hypertonic stress increases NFκB activity and NFκB activation is at least party responsible for AQP2 transcriptional repression on the onset of hypertonic stress.…”

mentioning

confidence: 99%

NF-κB Modulates Aquaporin-2 Transcription in Renal Collecting Duct Principal Cells

Cited by 70 publications

References 49 publications

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

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

Aldosterone Activates NF-κB in the Collecting Duct

An example of functional interaction between NFAT5/TonEBP and Nuclear Factor-κB by hypertonic stress: Aquaporin-2 transcription

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