Regulation of urothelial cell function by corticotrophin peptides

Abstract

Feline interstitial cystitis (FIC), a chronic idiopathic cystitis in cats, exhibits similarities to humans diagnosed with bladder pain syndrome/IC. In both syndromes, alterations in urothelial (UT) signaling/barrier may contribute to the associated pathophysiology. Corticotrophin peptides are involved in a number of functional pain syndromes and are now known to be expressed by peripheral tissues.Using time‐lapse fluorescence microscopy, we investigated a role for corticotrophin releasing factor (CRF), urocortin3 (UCN3), and receptors CRF‐1,‐2, in UT physiology. UT cells isolated from normal and FIC cat bladders were incubated with a membrane‐impermeant fluorescent dye (FM 1‐43; 5µM) and exposed to CRF (0.01µM), which has a greater affinity for CRF1. Normal UT exhibited a substantial membrane trafficking response (approximately 3 fold increase over basal/unstimulated) compared with FIC UT (1.5 fold increase over basal) .Both groups showed a low magnitude of trafficking in response to the selective CRF2 agonist, UCN3 (0.1µM).Astressin 2‐B alone (selective CRF2 antagonist; 1µM) evoked membrane trafficking in both groups; indicating cellular release of an autocrine factor, now free to act through CRF1 only. We also report a 'dis‐inhibition' of UT cell ATP release by astressin 2‐B and CRF mRNA expression by these cells. Our findings indicate a potential for CRF to play an important role in UT cell function.Funded byNIH R01 DK57284 and P50 DK64539