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

Abstract

Bladder pain syndrome (BPS) is a clinical syndrome of pelvic pain and urinary urgency-frequency in the absence of a specific cause. Investigating the expression levels of genes involved in the regulation of epithelial permeability , bladder contractility , and inflammation , we show that neurokinin (NK)1 and NK2 tachykinin receptors were significantly down-regulated in BPS patients. Tight junction proteins zona occludens-1 , junctional adherins molecule -1 , and occludin were similarly down-regulated , implicating increased urothelial permeability , whereas bradykinin B 1 receptor , cannabinoid receptor CB1 and muscarinic receptors M3-M5 were up-regulated. Using cellbased models , we show that prolonged exposure of NK1R to substance P caused a decrease of NK1R mRNA levels and a concomitant increase of regulatory micro(mi)RNAs miR-449b and miR-500. In the biopsies of BPS patients , the same miRNAs were significantly increased , suggesting that BPS promotes an attenuation of NK1R synthesis via activation of specific miRNAs. We confirm this hypothesis by identifying 31 differentially expressed miRNAs in BPS patients and demonstrate a direct correlation between miR-449b , miR-500 , miR-328 , and miR-320 and a down-regulation of NK1R mRNA and/or protein levels. Our findings further the knowledge of the molecular mechanisms of BPS , and have relevance for other clinical conditions involving the NK1 receptor. (Am J

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

“…The UA group consisted of patients with weak detrusor contractions (UA) or patients with acontractile detrusor and cystoscopy in line with obstruction. In all groups, 4 urothelium-covered muscle-containing biopsies were collected from the bladder dome by the same urologist and total RNA was isolated as described previously (12).…”

“…Normalized Ct values for 3-mRNA or 3-miRNA signatures of the samples with the known urodynamic status ( Figure 5, E and F) were employed in machine-based learning algorithms described in the Methods to train the model. Using the Ct values for either mRNA or miRNA signatures of the blinded samples as an input, the model allocated them to 3 groups corresponding to the predicted bladder functional state: BOO7, 24, 31, 32, 37, 38, 39, 40, 6, 5, 21, 22 and 23 belonged to the DO group; BOO16, 14, 15, 9, 8, 33, and 34 belonged to the BO group, and the remaining samples (BOO28, 29,30,41,42,10,11,12,13,17,18,19,20,4,3,2,1,25,26,27) were from the UA group. On the heatmaps, the samples were colored according to the machine-based group allocation (DO in blue, BO in green, and UA in orange) ( Figure 6, A and B).…”

“…Reliable markers of bladder function are urgently needed in order not to surpass the "point of no return," leading to bladder decompensation and failure. 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).…”

mir-500-Mediated GAD67 Downregulation Contributes to Neuropathic Pain

“…Furthermore, neuropathic pain generally involves the altered expression of many genes (Lacroix-Fralish et al, 2007) and it is likely that other genes in addition to Gad1 are also the targets of persistent pain-induced chromatin remodeling. GAD65 is another key rate-limiting-rate and is targeted preferentially to presynaptic terminals of central neurons for GABA synthesis (Tian et al, 1999;Patel et al, 2006). Studies have showed that GAD65 in different regions could participate in pain regulation by decreasing inhibition among neurons through reducing the levels of cellular GABA (Gwak and Hulsebosch, 2011;Zhang et al, 2011;Lorenzo et al, 2014).…”

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

“…However, in lower urinary tract dysfunction, this process is impaired by symptoms of urgency, frequency, and incomplete emptying. Lower urinary tract dysfunction causes profound changes in the gene expression profiles of both bladder urothelium and smooth muscle: in human bladder pain syndrome (BPS) 2 patients, the proteoglycan core proteins (1) and the tight junction proteins ZO-1, junctional adhesion molecule 1, and occludin (2) were down-regulated, implicating increased urothelial permeability. Bladder smooth muscle has a high level of plasticity and undergoes remodeling during lower urinary tract dysfunctions (3,4).…”