Integrated transcriptomic and proteomic analyses identify novel biomarkers of bladder outlet obstruction

Bladder outlet obstruction leads to pathological remodeling and emergence of lower urinary tract symptoms. Although relief of obstruction is associated with symptomatic improvement, it is not universally successful, reflecting persistent alterations in the bladder. Reliable surrogate biomarkers of obstruction are lacking, particularly early in the disease course before irreversible damage to the bladder may have occurred. In this study, re-analysis of publicly available transcriptomic datasets from diverse rodent models of obstruction identified tissue transcripts including Cthrc1, Grem1, Ltbp2, Acta1 and Msn that were induced in response to injury. Candidate markers were validated experimentally in an independent model of neurogenic obstruction demonstrating time-dependent changes, and a subset (GREM1, LTBP2, ACTA1, MSN) was increased in bladder tissue from pediatric patients with neurogenic bladder. Several candidates including CTHRC1, ACTA1 and MSN were also differentially abundant in independent proteomic datasets from a rat model of partial bladder outlet obstruction. Candidate markers were also attenuated in datasets from rats with either surgical removal of obstruction or treatment with anticholinergic medication or inosine. Integrated analysis of tissue transcriptomics data and tissue and urine proteomics data from a model of neurogenic obstruction revealed modest but statistically significant concordance between markers observed in tissue and urine. These findings identify tissue and urine biomarkers of both non-neurogenic and neurogenic obstruction that may reflect early changes in obstructive uropathy that could be monitored in a non-invasive manner.