Abstract
Bladder outlet obstruction (BOO) is a common urologic disease associated with poorly understood molecular mechanisms. This study aimed to investigate the possible involvements of circRNAs (circular RNAs) and circRNA-encoded proteins in BOO development. The rat BOO model was established by the partial bladder outlet obstruction surgery. Differential expression of circRNA and protein profiles were characterized by deep RNA sequencing and iTRAQ quantitative proteomics respectively. Novel proteins encoded by circRNAs were predicted through ORF (open reading frame) selection using the GETORF software and verified by the mass spectrometry in proteomics, combined with the validation of their expressional alterations by quantitative RT-PCR. Totally 3,051 circRNAs were differentially expressed in bladder tissues of rat BOO model with widespread genomic distributions, including 1,414 up-regulated, and 1,637 down-regulated circRNAs. Our following quantitative proteomics revealed significant changes of 85 proteins in rat BOO model, which were enriched in multiple biological processes and signaling pathways such as the PPAR and Wnt pathways. Among them, 21 differentially expressed proteins were predicted to be encoded by circRNAs and showed consistent circRNA and protein levels in rat BOO model. The expression levels of five protein-encoding circRNAs were further validated by quantitative RT-PCR and mass spectrometry. The circRNA and protein profiles were substantially altered in rat BOO model, with great expressional changes of circRNA-encoded novel proteins.
Highlights
Bladder outlet obstruction (BOO) is a urological condition featured by voiding difficulty, abdominal straining during voiding, increased postvoid residual and reduced urine flow rate due to increased detrusor pressure, and which is usually associated with lower urinary tract symptoms (LUTS) (Meier and Padmanabhan, 2016; Niemczyk et al, 2018)
In our RNA sequencing assay, we found that the lengths of circRNAs identified in rat bladder tissues range from 100 to over 3,000 bp, and the greatest enrichment of circRNAs length near 400 bp was observed in the circRNA profile in the rat bladder tissues (Figure 1B)
The pathogenesis and progression of BOO was previously known to be closely associated with multiple anatomic, functional and neurologic factors which contributed to urothelium abnormality such as intrafascicular fibrosis (King and Goldman, 2014; Meier and Padmanabhan, 2016; Fusco et al, 2018), the molecular events driving the pathogenic alterations in urothelium during BOO development still remains poorly understood
Summary
Bladder outlet obstruction (BOO) is a urological condition featured by voiding difficulty, abdominal straining during voiding, increased postvoid residual and reduced urine flow rate due to increased detrusor pressure, and which is usually associated with lower urinary tract symptoms (LUTS) (Meier and Padmanabhan, 2016; Niemczyk et al, 2018). It is known that BOO pathogenesis could be induced by anatomic factors including benign prostatic obstruction (BPO), pelvic organ prolapses, stricture diseases, urologic malignancies and iatrogenic obstruction, as well as functional causes such as dysfunctional voiding, primary bladder neck obstruction, and Fowler’s syndrome (King and Goldman, 2014; Meier and Padmanabhan, 2016; Fusco et al, 2018). Recent studies showed that the progression and persistence of BOO usually resulted into various morphological and molecular alterations in the urothelium, such as severe urothelial dysfunctions and cell apoptosis in suburothelium, associated with great changes in signaling pathways and interruption of barrier, transport, and sensory functions in urothelium (Fusco et al, 2018; Niemczyk et al, 2018). The molecular mechanism of BOO pathophysiology is still not well elucidated
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