Abstract
Transforming growth factor (TGF)-β1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-β/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO) is yet to be conclusively. Using a rat PBOO model, we investigated TGF-β1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS) could inhibit TGF-β/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty-eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16), PBOO operation without STS treatment group (n = 16) and PBOO operation with STS treatment group (n = 16). Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16) or vehicle (n = 16) two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF-β/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR). One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-β1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (α-SMA), collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-β/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO operation.
Highlights
Partial urinary bladder outlet obstruction (PBOO) is frequently observed in various clinical diseases such as benign prostate hyperplasia (BPH), neurogenic bladder, bladder neck stricture or posterior urethral stenosis
Paraffin-embedded sections from partial bladder outlet obstruction (PBOO) operation without sodium tanshinone IIA sulfonate (STS) treatment group and PBOO operation with STS treatment groups were stained with hematoxylin and eosin and examined
reverse transcriptase polymerase chain reaction (RT-PCR) analysis showed that α-SMA, collagen I, and collagen III expression were decreased in PBOO rats with STS treatment rats at weeks 4 and 8 (P
Summary
Partial urinary bladder outlet obstruction (PBOO) is frequently observed in various clinical diseases such as benign prostate hyperplasia (BPH), neurogenic bladder, bladder neck stricture or posterior urethral stenosis. The development of bladder wall tissue fibrosis in the setting of partial outlet obstruction is thought to be due to increased levels of nerve growth factor, basic fibroblast growth factor, connective tissue growth factor or transforming growth factorβ1(TGF-β1)[2,3,4,5]. It initiates intracellular responses by binding to the specific transmembrane receptors which have intracellular serine/threonine kinase activity [6] These activated receptors further lead to phosphorylation of receptor-associated Smad2/3 proteins, which are capable of combining with Smad. A study using a 6-week bladder outlet obstruction model, demonstrated increase in the the weight of bladder tissue and decrease in that the detrusor contractile force, which was accompanied by a significant increase in urine TGF-β1 [7]. Blockage of the TGF-β/Smad signaling pathway by using various strategies such as anti-transforming growth factor (TGF)-β1 antibody, tanshinone II A, microRNAs and small interfering RNA have provided vital evidence pointing towards the crucial role of the pathway in development of fibrosis in various tissues and organs [9,10,11,12]
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