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Characterization of global and region-specific transcriptomic alterations in the porcine bladder following acute partial bladder outlet obstruction

ABSTRACT: Partial bladder outlet obstruction (pBOO) is a progressive fibroproliferative disorder that results in poorly compliant, high-pressure bladders due to lower urinary tract occlusion. To date, the mechanisms governing pBOO-induced bladder remodeling remain poorly understood. The goals of the present study were to profile global and region-specific transcriptomes of porcine bladders in response to acute pBOO using RNA sequencing and to identify genes and pathways differentially affected in the bladder dome and trigone by obstructive injury. Nine adult female, Yucatan mini-swine were randomized and divided into either nonsurgical controls (n=5) or those subjected to pBOO for 4 weeks (n=4). Post-pBOO swine demonstrated bladder smooth muscle hypertrophy as well as significant declines in bladder capacity (35±7% of baseline) and compliance (38±10% of baseline). The global transcriptome of obstructed bladders revealed enrichment of processes related to loss of urothelial barrier function, immune activation, cell cycle regulation, extracellular matrix organization, and signal transduction similar to human and rodent evaluations of pBOO. Moreover, our data also showed that adaptive responses to pBOO are regionally dependent rather than globally uniform, with zonal-specific divergence observed across hypoxic, fibrotic, metabolic, and neuronal pathways between the obstructed dome and trigone. These results highlight the regional heterogeneity of bladder responses to obstructive urologic disease and therefore may inform future intravesical therapies based on zonal drug targeting.

ORGANISM(S): Sus scrofa

PROVIDER: GSE337305 | GEO | 2026/08/26

REPOSITORIES: GEO

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Project description:Recent studies in our lab have identified a mutant mouse model of obstructive nephropathy designated mgb for megabladder. Homozygotic mgb mice (mgb-/-) develop lower urinary tract obstruction in utero due to a lack of bladder smooth muscle differentiation. This defect is the result of a random transgene insertion into chromosome 16 followed by a translocation of this fragment into chromosome 11. In an effort to identify potential gene targets affected in mgb mice, we performed transcriptional profiling on embryonic day 15 (E15) mgb-/- bladders using both a Chromosome 11/16 Custom GeneChip Array and the Affymetrix Mouse Genome 430 2.0 GeneChip. This analysis identified no definitive mis-expressed gene targets on chromosome 11. In contrast, mgb-/- mice significantly over-expressed a cluster of gene products located on the translocated fragment of chromosome 16 including urotensin II-related peptide (Urp), which was shown to be preferentially over-expressed in developing mgb-/- bladders. Immunohistochemical studies indicated that the spatial distribution of Urp was altered in mgb-/- bladders, while biochemical studies suggested a potential role for Urp in modifying smooth muscle cell phenotype in vitro. Pathway analysis of mgb microarray data showed dysregulation of at least 60 gene products associated with the differentiation of smooth muscle. In conclusion, the results of this study indicate that the molecular pathways controlling normal smooth muscle development are severely altered in mgb-/- bladders, and provide the first evidence that Urp may play a critical role in bladder smooth muscle development. Keywords: mgb mutant bladders Gene expression profiling was performed on two separate study groups. First, total cellular RNA was isolated from wildtype (n=2; 1 female/1 male), mgb+/- (n=2; 1 female/1 male), and mgb-/- (n=2; 1 female/1 male) E15 whole embryos. Second, total cellular RNA was isolated from the bladders of E15 wildtype (n=7; 3 female/4 male), mgb+/- mice (n=7; 3 female/4 male), and mgb-/- mice (n=11; 7 females/4 males).

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Characterization of global and region-specific transcriptomic alterations in the porcine bladder following acute partial bladder outlet obstruction

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