Presentation Authors: Dale Bjorling*, Zun-Yi Wang, Madison, WI, Yongfeng Gong, Jinghui Hou, St. Louis, MO
Introduction: MicroRNAs (miRNA) are short (19-25 nucleotides), non-coding RNA sequences that bind to the 3â€™ untranslated region of various messenger RNA (mRNA), accelerating mRNA degradation or preventing translation of the encoded protein. MicroRNA-29 or miR-29 suppresses translation of genes related to extracellular matrix (ECM) formation, particularly various collagens, collagen cross-linking elements, and enzymes that regulate post-translational modification of the ECM proteins. Dysregulation of ECM formation results in fibrosis. A recent study comprehensively investigated miRNA abundance and signaling in bladder biopsies from patients with bladder outlet obstruction and found significant increases or decreases in multiple miRNAs, but specifically reported a decrease in miR-29.
Methods: Bladder outlet obstruction (BOO) was created in male C57BL/6 mice, and mice were sacrificed 10 days later. Abundance of miR-29a in the urothelium and detrusor was determined, as was abundance of mRNA encoding for transforming growth factor-Î² (TGFÎ²), collagen 1Î±1 (col 1a1), collagen 4Î±1 (col 4a1), connective tissue growth factor (CTGF), fibronectin-1 (FBN1), and laminin C1 (LAM). In two other groups, mice were injected with miR-29a mimic or vehicle (6 treatments at 25 Âµg/treatment given ip beginning 24 hr before creation of BOO, repeated on the day of surgery, and 2, 4, 6, and 8 days after surgery) and sacrificed 10 days after creation of BOO.
Results: The abundance of miR-29a was decreased in the detrusor, but not the urothelium, after 10 days of BOO. mRNA encoding for TGFÎ², col 1a1, col 4a1, FBN1, and LAM were all ignificantly increased in the detrusor of mice with BOO compared to sham-operated controls. Message for CTGF was increased in both the detrusor and urothelium. Injection of mice with miR-29a mimic decreased message for col 1a1 and LAM in both the urothelium and detrusor, as well as message for FBN1 in the detrusor, compared to BOO mice treated with vehicle.
Conclusions: These results indicate: 1. abundance of miR-29a is decreased by BOO; and 2. miR-29a has the capacity to decrease message for components of fibrosis in the presence of BOO. Further research is required, but these experiments support consideration of miR-29a as a potential therapy to prevent or treat BOO-associated bladder fibrosis.
Source of Funding: NIH U54DK104310; NIH R01DK084059