title: Aldosterone regulates microRNAs in the cortical collecting duct to alter sodium transport.
abstract: A role for microRNAs (miRs) in the physiologic regulation of sodium transport in the kidney has not been established. In this study, we investigated the potential of aldosterone to alter miR expression in mouse cortical collecting duct (mCCD) epithelial cells. Microarray studies demonstrated the regulation of miR expression by aldosterone in both cultured mCCD and isolated primary distal nephron principal cells. Aldosterone regulation of the most significantly downregulated miRs, mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983 was confirmed by quantitative RT-PCR. Reducing the expression of these miRs separately or in combination increased epithelial sodium channel (ENaC)-mediated sodium transport in mCCD cells, without mineralocorticoid supplementation. Artificially increasing the expression of these miRs by transfection with plasmid precursors or miR mimic constructs blunted aldosterone stimulation of ENaC transport. Using a newly developed computational approach, termed ComiR, we predicted potential gene targets for the aldosterone-regulated miRs and confirmed ankyrin 3 (Ank3) as a novel aldosterone and miR-regulated protein. A dual-luciferase assay demonstrated direct binding of the miRs with the Ank3-3' untranslated region. Overexpression of Ank3 increased and depletion of Ank3 decreased ENaC-mediated sodium transport in mCCD cells. These findings implicate miRs as intermediaries in aldosterone signaling in principal cells of the distal kidney nephron.
authors.affiliation: Renal-Electrolyte Division.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Edinger
authors.affiliation: Computational and Systems Biology.
authors.forename: Claudia
authors.initials: C
authors.lastname: Coronnello
authors.affiliation: Division of Nephrology, Department of Pediatrics.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bodnar
authors.forename: Mariana
authors.initials: M
authors.lastname: Labarca
authors.forename: Vivek
authors.initials: V
authors.lastname: Bhalla
authors.affiliation: Department of Pathology, and.
authors.forename: William A
authors.initials: WA
authors.lastname: LaFramboise
authors.affiliation: Computational and Systems Biology.
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Benos
authors.affiliation: Division of Nephrology, Department of Pediatrics.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ho
authors.affiliation: Renal-Electrolyte Division, Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John P
authors.initials: JP
authors.lastname: Johnson
authors.affiliation: Renal-Electrolyte Division, Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania michael7@pitt.edu.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Butterworth
mesh_terms: D000450:Aldosterone / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000378:metabolism; D007672:Kidney Cortex / Q000166:cytology / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009399:Nephrons / Q000166:cytology / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012964:Sodium / Q000378:metabolism*
chemical_list: C094681:Ank3 protein, mouse; D017487:Ankyrins; D053503:Epithelial Sodium Channels; C000594122:MIRN1983 microRNA, mouse; C547384:MIRN290 microRNA, mouse; D035683:MicroRNAs; C541986:Mirn335 microRNA, mouse; D034741:RNA, Small Interfering; D000450:Aldosterone; D012964:Sodium; D008156:Luciferases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
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