{"doi":"10.3389/fphys.2022.816959","title":"Glucocorticoid Receptor Maintains Vasopressin Responses in Kidney Collecting Duct Cells","abstract":"<jats:p>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 <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> gene transcription. However, TNF or TGFβ blunted the vasopressin-induced <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> gene expression.</jats:p>","journal":"Frontiers in Physiology","year":2022,"id":655085,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1709878,"name":"Shih-Han Su","orcid":null,"position":1,"is_corresponding":false},{"id":1709879,"name":"Cheng-Hsuan Ho","orcid":null,"position":2,"is_corresponding":false},{"id":1709880,"name":"Ai-Hsin Yeh","orcid":null,"position":3,"is_corresponding":false},{"id":1709881,"name":"Yi-Jiun Lin","orcid":null,"position":4,"is_corresponding":false},{"id":1709882,"name":"Ming-Jiun Yu","orcid":null,"position":5,"is_corresponding":false},{"id":1709877,"name":"Hsiu-Hui Yang","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Glucocorticoid Receptor Maintains Vasopressin Responses in Kidney Collecting Duct Cells","abstract":"<jats:p>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 <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> gene transcription. However, TNF or TGFβ blunted the vasopressin-induced <jats:italic>Aqp2</jats:italic> 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 <jats:italic>Aqp2</jats:italic> gene expression.</jats:p>","is_dataset_classified":null,"base_score":1.791759469228055,"endowment":1.791759469228055,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35685285","pmcid":"PMC9173664","openalex_id":"https://openalex.org/W4281387981","authors":[],"funders":[],"total_grants":0,"fwci":0.3926,"citation_percentile":0.53666,"influential_citations":0,"citation_trend":[{"year":2023,"count":3},{"year":2025,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/articles/10.3389/fphys.2022.816959/pdf","host_type":"journal"},{"url":"https://www.frontiersin.org/articles/10.3389/fphys.2022.816959/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fphys.2022.816959/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fphys.2022.816959","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35685285","host_type":"repository"},{"url":"https://doaj.org/article/0b56cbdc4dc149a1899d92b8ce4763ae","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/9173664","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC9173664","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC9173664?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Ion Transport and Channel Regulation","Electrolyte and hormonal disorders","Renal and related cancers"],"mesh_terms":[],"keywords":["Vasopressin","Gene knockdown","Arginine vasopressin receptor 2","Aquaporin 2","Glucocorticoid receptor","Biology","Vasopressin receptor","Arginine vasopressin receptor 1B","Downregulation and upregulation","Endocrinology","Glucocorticoid","Internal medicine","Cell biology","Receptor","Medicine","Gene","Biochemistry","TNF","Aquaporin-2","Collecting Duct","Tgfβ"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Clean water and sanitation"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T09:37:17.764621Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}