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.

Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction

“…The studies of individual cellular signaling pathways conducted in animal models (5-7) identified some of the regulated genes typical for a specific symptomatic state; similarly, a number of regulatory miRNAs have been implicated in bladder pathologies (8)(9)(10)(11)(12) and function (13). Increasing evidence indicates that miRNAs may play a role in the regulation of urothelial permeability (14) and bladder contractility (15,16).…”

MicroRNA MiR-199a-5p Regulates Smooth Muscle Cell Proliferation and Morphology by Targeting WNT2 Signaling Pathway

“…Previously, we identified miR-199a-5p as an important regulator of intercellular junctions (17). Upon overexpression in urothelial cells, it impairs correct tight junction formation and leads to increased permeability.…”

“…Our previous laser microdissection studies have shown that miR-199a-5p was predominantly expressed in bladder smooth muscle (17). We sought to elucidate its function in the bladder smooth muscle cells (SMCs) and investigated the effects of the alteration of its levels with antimiR-and miR-overexpressing lentiviral vectors on the smooth muscle morphology.…”

Role of MicroRNA in Visceral Pain

“…Monastyrskaya et al also documented a possible link between miR-199a-5p and the control of urothelial permeability in bladder pain syndrome. 101 In urothelial cells, overexpression of miR-199a demonstrated impairment in tight junction formation resulting in increased epithelial permeability. Differences in miRNAs expression have also been reported in endometrium between patients with and without painful endometriosis.…”

“…This finding strongly suggests the involvement of miRNAs in long-term cortical plasticity following esophageal acid exposure early in life. Here, we review specific miRNAs that have been identified as the regulators of nociceptive activity and highlight their possible association with pain processing in various pain conditions (Table 87, 99,100,101,103,[105][106][107][108][109][110][111][112][113][114][115][116][117][118][119][120][121][122] ).…”