MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome

Veronica Sanchez Freire^*, Fiona C. Burkhard, Thomas M. Kessler, Annette Kuhn, Annette Draeger^* and Katia Monastyrskaya^*

From the Department of Cell Biology,^* Institute of Anatomy, University of Bern, Bern, and the Departments of Urology, and Gynaecology, University Hospital, Bern, Switzerland

Bladder pain syndrome (BPS) is a clinical syndrome of pelvicpain and urinary urgency-frequency in the absence of a specificcause. Investigating the expression levels of genes involvedin the regulation of epithelial permeability, bladder contractility,and inflammation, we show that neurokinin (NK)1 and NK2 tachykininreceptors were significantly down-regulated in BPS patients.Tight junction proteins zona occludens-1, junctional adherinsmolecule -1, and occludin were similarly down-regulated, implicatingincreased urothelial permeability, whereas bradykinin B₁ receptor,cannabinoid receptor CB1 and muscarinic receptors M3-M5 wereup-regulated. Using cell-based models, we show that prolongedexposure of NK1R to substance P caused a decrease of NK1R mRNAlevels and a concomitant increase of regulatory micro(mi)RNAsmiR-449b and miR-500. In the biopsies of BPS patients, the samemiRNAs were significantly increased, suggesting that BPS promotesan attenuation of NK1R synthesis via activation of specificmiRNAs. We confirm this hypothesis by identifying 31 differentiallyexpressed miRNAs in BPS patients and demonstrate a direct correlationbetween miR-449b, miR-500, miR-328, and miR-320 and a down-regulationof NK1R mRNA and/or protein levels. Our findings further theknowledge of the molecular mechanisms of BPS, and have relevancefor other clinical conditions involving the NK1 receptor.