AN EARLY MOLECULAR RESPONSE INDUCED BY ACUTE OVERDISTENSION OF THE RABBIT URINARY-BLADDER

In the rabbit, partial urinary bladder outlet obstruction rapidly increases bladder mass and alters several parameters of normal bladder function. Previous experiments on this animal model (Buttyan et al. Neurourol. Urodyn. 11: 225-238, 1992) had identified an early molecular response to partial outlet obstruction that involved the profound induction of mRNA encoding a heat-shock gene, hsp-70, as well as induced expression of mRNA for basic fibroblast growth factor and certain protooncogenes. Numerous physiological studies of the hypertrophied rabbit bladder indicate that the primary stimulus for bladder growth may be the initial overdistension that occurs as the bladder fills following partial outlet obstruction. The present study was undertaken to determine if the sequence and characteristics of gene activation during the recovery following a brief period of overdistension of the rabbit bladder are comparable with the gene activity previously described in association with partial outlet obstruction. Rabbit bladders were overdistended to 20% above capacity for 1 hr and then relieved. Bladders were recovered from control (untreated) rabbits and from rabbits at 1 hr or at 1, 3 or 5 days following relief of overdistension. RNAs extracted from these tissues were examined by Northern blot assays for a number of different mRNA transcripts previously shown to be altered by partial outlet obstruction. By 1 hr following the relief from acute overdistension, there was already a greater than 10-fold increase in the expression of hsp-70 related transcripts as well as a marked increase in the expression of mRNA encoding bFGF and decreased expression of TGF-beta(1). Additionally, expression of the early response genes, c-fos and c-jun were induced at this time. By 24 hrs following overdistension, the expression of all genes returned to near control levels. These results were reproduced for individual specimens from two groups of treated rabbits. In summary, a brief interval of overdistension of the rabbit bladder induces specific alterations in gene activity during the subsequent recovery period that mimics the activity associated with partial outlet obstruction. These results are consistent with the hypothesis that the changes observed following partial outlet obstruction are caused by an initial overdistension of the urinary bladder wall.