title: miR-199a-5p regulates urothelial permeability and may play a role in bladder pain syndrome.
abstract: Defects in urothelial integrity resulting in leakage and activation of underlying sensory nerves are potential causative factors of bladder pain syndrome, a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. Herein, we identified the microRNA miR-199a-5p as an important regulator of intercellular junctions. On overexpression in urothelial cells, it impairs correct tight junction formation and leads to increased permeability. miR-199a-5p directly targets mRNAs encoding LIN7C, ARHGAP12, PALS1, RND1, and PVRL1 and attenuates their expression levels to a similar extent. Using laser microdissection, we showed that miR-199a-5p is predominantly expressed in bladder smooth muscle but that it is also detected in mature bladder urothelium and primary urothelial cultures. In the urothelium, its expression can be up-regulated after activation of cAMP signaling pathways. While validating miR-199a-5p targets, we delineated novel functions of LIN7C and ARHGAP12 in urothelial integrity and confirmed the essential role of PALS1 in establishing and maintaining urothelial polarity and junction assembly. The present results point to a possible link between miR-199a-5p expression and the control of urothelial permeability in bladder pain syndrome. Up-regulation of miR-199a-5p and concomitant down-regulation of its multiple targets might be detrimental to the establishment of a tight urothelial barrier, leading to chronic pain.
authors.affiliation: Urology Research Laboratory, Department of Clinical Research, University of Bern, Bern, Switzerland. monastyk@dkf.unibe.ch
authors.forename: Katia
authors.initials: K
authors.lastname: Monastyrskaya
authors.forename: Verónica
authors.initials: V
authors.lastname: Sánchez-Freire
authors.forename: Ali
authors.initials: A
authors.lastname: Hashemi Gheinani
authors.forename: David J
authors.initials: DJ
authors.lastname: Klumpp
authors.forename: Eduard B
authors.initials: EB
authors.lastname: Babiychuk
authors.forename: Annette
authors.initials: A
authors.lastname: Draeger
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Burkhard
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D018856:Cystitis, Interstitial / Q000235:genetics* / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D017097:Electric Impedance; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D011485:Protein Binding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D062725:Tight Junction Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D019459:Urothelium / Q000378:metabolism* / Q000473:pathology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D062725:Tight Junction Proteins; C531408:mirn199 microRNA, human; D000242:Cyclic AMP; D008156:Luciferases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein