Bayesian identification of candidate transcription factors for the regulation of <i>Aqp2</i> gene expression

Kikuchi, Hiroaki; Jung, Hyun Jun; Raghuram, Viswanathan; Leo, Kirby T.; Park, Eui‐Jung; Yang, Chuanchuan; Chou, Chun Lin; Chen, Lihe; Knepper, Mark A.

doi:10.1152/ajprenal.00204.2021

Cited by 14 publications

(15 citation statements)

References 56 publications

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“…However, recent ChIP-seq analysis of the re-cloned mpkCCD cells that express all necessary molecular components for vasopressin signaling, AQP2 gene expression, and trafficking ( Rinschen et al, 2010 ; Xie et al, 2010 ; Khositseth et al, 2011 ; Schenk et al, 2012 ; Loo et al, 2013 ) showed no clear evidence of Creb1’s involvement in AQP2 transcription ( Jung et al, 2018 ). Instead, a number of other transcription factor candidates were suggested for future investigation ( Kikuchi et al, 2021 ), preferentially with CRISPR/Cas9-based gene knockout ( Isobe et al, 2017 , 2020 ; Datta et al, 2020 ) or small hairpin RNA-mediated gene knockdown when gene deletion is lethal ( Wang et al, 2017 , 2020 ; Kuo et al, 2018 ; Lin et al, 2019 ; Wong et al, 2020 ). Thus, a comprehensive AQP2 transcription network may be anticipated with the advent of the systems approaches that generate novel hypotheses addressable with modern molecular biological methods.…”

Section: Discussionmentioning

confidence: 99%

α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

Yang

et al. 2021

Front. Physiol.

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Water permeability of the kidney collecting ducts is regulated by the peptide hormone vasopressin. Between minutes and hours (short-term), vasopressin induces trafficking of the water channel protein aquaporin-2 to the apical plasma membrane of the collecting duct principal cells to increase water permeability. Between hours and days (long-term), vasopressin induces aquaporin-2 gene expression. Here, we investigated the mechanisms that bridge the short-term and long-term vasopressin-mediated aquaporin-2 regulation by α-actinin 4, an F-actin crosslinking protein and a transcription co-activator of the glucocorticoid receptor. Vasopressin induced F-actin depolymerization and α-actinin 4 nuclear translocation in the mpkCCD collecting duct cell model. Co-immunoprecipitation followed by immunoblotting showed increased interaction between α-actinin 4 and glucocorticoid receptor in response to vasopressin. ChIP-PCR showed results consistent with α-actinin 4 and glucocorticoid receptor binding to the aquaporin-2 promoter. α-actinin 4 knockdown reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. α-actinin 4 knockdown did not affect vasopressin-induced glucocorticoid receptor nuclear translocation, suggesting independent mechanisms of vasopressin-induced nuclear translocation of α-actinin 4 and glucocorticoid receptor. Glucocorticoid receptor knockdown profoundly reduced vasopressin-induced increases in aquaporin-2 mRNA and protein expression. In the absence of glucocorticoid analog dexamethasone, vasopressin-induced increases in glucocorticoid receptor nuclear translocation and aquaporin-2 mRNA were greatly reduced. α-actinin 4 knockdown further reduced vasopressin-induced increase in aquaporin-2 mRNA in the absence of dexamethasone. We conclude that glucocorticoid receptor plays a major role in vasopressin-induced aquaporin-2 gene expression that can be enhanced by α-actinin 4. In the absence of vasopressin, α-actinin 4 crosslinks F-actin underneath the apical plasma membrane, impeding aquaporin-2 membrane insertion. Vasopressin-induced F-actin depolymerization in one hand facilitates aquaporin-2 apical membrane insertion and in the other hand frees α-actinin 4 to enter the nucleus where it binds glucocorticoid receptor to enhance aquaporin-2 gene expression.

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Section: Discussionmentioning

confidence: 99%

α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

Yang

et al. 2021

Front. Physiol.

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“…The present study represents such an example. Previous system approaches have alluded to the role of glucocorticoid receptor in the Aqp2 gene expression in the kidney collecting duct cells ( Yu et al, 2009 ; Kikuchi et al, 2021 ). In line with this, glucocorticoid receptor agonist dexamethasone increases the vasopressin-induced Aqp2 gene expression in the collecting duct mpkCCD cells ( Kuo et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Recent ChIP-seq analysis showed the indirect involvement of Creb1 in Aqp2 gene transcription ( Jung et al, 2018 ). A number of other transcription factor candidates were suggested for future investigation ( Kikuchi et al, 2021 ), preferentially with CRISPR/Cas9-based gene knockout ( Isobe et al, 2017 ; Datta et al, 2020 ; Isobe et al, 2020 ) or small hairpin RNA-mediated gene knockdown when gene knockout is lethal ( Wang et al, 2017 ; Kuo et al, 2018 ; Lin et al, 2019 ; Wang et al, 2020 ; Wong et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Receptor Maintains Vasopressin Responses in Kidney Collecting Duct Cells

Yang

et al. 2022

Front. Physiol.

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Water permeability of the kidney collecting ducts is regulated in part by the amount of the molecular water channel protein aquaporin-2 (AQP2), whose expression, in turn, is regulated by the pituitary peptide hormone vasopressin. We previously showed that stable glucocorticoid receptor knockdown diminished the vasopressin-induced Aqp2 gene expression in the collecting duct cell model mpkCCD. Here, we investigated the pathways regulated by the glucocorticoid receptor by comparing transcriptomes of the mpkCCD cells with or without stable glucocorticoid receptor knockdown. Glucocorticoid receptor knockdown downregulated 5,394 transcripts associated with 55 KEGG pathways including “vasopressin-regulated water reabsorption,” indicative of positive regulatory roles of these pathways in the vasopressin-induced Aqp2 gene expression. Quantitative RT-PCR confirmed the downregulation of the vasopressin V2 receptor transcript upon glucocorticoid receptor knockdown. Glucocorticoid receptor knockdown upregulated 3,785 transcripts associated with 42 KEGG pathways including the “TNF signaling pathway” and “TGFβ signaling pathway,” suggesting the negative regulatory roles of these pathways in the vasopressin-induced Aqp2 gene expression. Quantitative RT-PCR confirmed the upregulation of TNF and TGFβ receptor transcripts upon glucocorticoid receptor knockdown. TNF or TGFβ inhibitor alone, in the absence of vasopressin, did not induce Aqp2 gene transcription. However, TNF or TGFβ blunted the vasopressin-induced Aqp2 gene expression. In particular, TGFβ reduced vasopressin-induced increases in Akt phosphorylation without inducing epithelial-to-mesenchymal transition or interfering with vasopressin-induced apical AQP2 trafficking. In summary, our RNA-seq transcriptomic comparison revealed positive and negative regulatory pathways maintained by the glucocorticoid receptor for the vasopressin-induced Aqp2 gene expression.

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“…As described above, the short-term effect of vasopressin is exerted by AQP2 translocation from the intracellular vesicles to the apical membrane. Furthermore, vasopressin can induce water reabsorption for 24 h or more by enhancing AQP2 transcription and its protein abundance in the collecting duct cells [ 16 , 17 ].…”

Section: Upon Vasopressin Stimulation Aqp2 Increases Water Reabsorption and Urine Concentrationmentioning

confidence: 99%

Updates and Perspectives on Aquaporin-2 and Water Balance Disorders

Noda

Sasaki

2021

IJMS

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Ensuring the proper amount of water inside the body is essential for survival. One of the key factors in the maintenance of body water balance is water reabsorption in the collecting ducts of the kidney, a process that is regulated by aquaporin-2 (AQP2). AQP2 is a channel that is exclusively selective for water molecules and impermeable to ions or other small molecules. Impairments of AQP2 result in various water balance disorders, including nephrogenic diabetes insipidus (NDI), which is a disease characterized by a massive loss of water through the kidney and consequent severe dehydration. Dysregulation of AQP2 is also a cause of water retention with hyponatremia in heart failure, hepatic cirrhosis, and syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone vasopressin is an upstream regulator of AQP2. Its binding to the vasopressin V2 receptor promotes AQP2 targeting to the apical membrane and thus enables water reabsorption. Tolvaptan, a vasopressin V2 receptor antagonist, is effective and widely used for water retention with hyponatremia. However, there are no studies showing improvement in hard outcomes or long-term prognosis. A possible reason is that vasopressin receptors have many downstream effects other than AQP2 function. It is expected that the development of drugs that directly target AQP2 may result in increased treatment specificity and effectiveness for water balance disorders. This review summarizes recent progress in studies of AQP2 and drug development challenges for water balance disorders.

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Bayesian identification of candidate transcription factors for the regulation of Aqp2 gene expression

Cited by 14 publications

References 56 publications

α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

α-Actinin 4 Links Vasopressin Short-Term and Long-Term Regulation of Aquaporin-2 in Kidney Collecting Duct Cells

Glucocorticoid Receptor Maintains Vasopressin Responses in Kidney Collecting Duct Cells

Updates and Perspectives on Aquaporin-2 and Water Balance Disorders

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