Pirfenidone attenuates bladder fibrosis and mitigates deterioration of bladder function in a rat model of partial bladder outlet obstruction

Abstract

To investigate the effects of pirfenidone (PFD) on the attenuation of bladder remodeling, and the associated functional changes caused by partial bladder outlet obstruction (pBOO), the present study performed surgery on adult male Sprague‑Dawley rats produce a model of pBOO. The rats in the pBOO group were administered a placebo and, in the CMC group, PFD mixed with the placebo was administered orally at 500 mg/kg body weight each day for 5 weeks, from 1 week after surgery. The rat bladders were harvested for biochemical analysis following cystometry at the end of the 6 week period. The histopathology was determined using Masson's trichrome staining. The mRNA and protein levels of pro‑fibrotic growth factors and extracellular matrix subtypes were assessed. pBOO debilitated bladder function and caused the parameters from cystometry to increase significantly compared with those in the control group (P<0.05), which were mitigated significantly following PFD treatment (P<0.05). In terms of the histology, the rats in the pBOO group exhibited significant increases in bladder weight, muscle hypertrophy and deposition of collagens, which were suppressed by PFD treatment (P<0.05). Based on the biochemical analysis, significant increases in the mRNA levels of collagen subtypes and growth factors, and protein levels of profibrotic growth factors and α‑smooth muscle actin in the bladders of rats in the pBOO group were reduced following PFD treatment. PFD prevented bladder remodeling and attenuated bladder fibrosis and, therefore, mitigated the deterioration of bladder function during the initial stage of pBOO.

Antifibrosis treatment by inhibition of VEGF, FGF, and PDGF receptors improves bladder wall remodeling and detrusor overactivity in association with modulation of C‐fiber afferent activity in mice with spinal cord injury

“…Several studies have reported that competitive inhibition of TGF-β or blockage of the TGF-β receptors could preserve the bladder function. 6,7 However, some other studies have reported that anti-TGF-β therapy could be tumorigenic because of its pleiotropic nature. 8 Nintedanib, which inhibits the receptors of other fibrosis-related factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and plateletderived growth factor (PDGF), shows a lower risk in tumor promotion and approved as a therapeutic agent for idiopathic pulmonary fibrosis patients.…”

Pirfenidone suppresses TGF‑β1‑induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway

“…Pirfenidone (PFD), a novel anti-fibrotic drug, has shown potent antifibrotic efficacy in many organs, such as lung ( 11 ), liver ( 12 ), kidney ( 13 ), heart ( 14 ), and bladder ( 15 ). Additionally, it can inhibit cell proliferation and/or activation of different fibroblasts, including human Tenon's fibroblasts ( 16 ), rat renal fibroblasts ( 17 ), and rat cardiac fibroblasts ( 14 ), as well as downregulation of a series of cytokines, including TGF-β1 and connective tissue growth factor (CTGF) ( 18 ).…”

Urinary bladder organ hypertrophy is partially regulated by Akt1-mediated protein synthesis pathway

“…We demonstrate that up-regulation of Akt leads to excessive protein production of type I collagen and αSMA in the hypertrophic urinary bladder, however, the increased PCNA levels in urothelium is not regulated by Akt. It is reported that at 6 weeks of pBOO, the up-regulation of type I and type III collagen mRNA and protein are observed in the hypertrophic urinary bladder (Duan et al, 2015, Kim et al, 2000). At 2 weeks of pBOO, we only observe an up-regulation of collagen protein but not mRNA in the urinary bladder, and in the same sample we detect an Akt-independent up-regulation of PCNA mRNA levels.…”

“…In clinical studies, bladder wall thickness is considered as a non-invasive and effective test to evaluate patients with lower urinary tract obstruction, and is suggested to be useful for showing the effectiveness of drug treatment (Karakose et al, 2014). Bladder wall thickening is manifested by multiple factors including but not limit to alterations of urothelium metabolic properties, inflammatory responses, fibrosis, and detrusor muscle remodeling (Duan et al, 2015, Kanno et al, 2016, Metcalfe et al, 2010, Michishita et al, 2015, Mirone et al, 2007, Roosen et al, 2009). Understanding of the molecular changes in the thickened bladder wall can provide fundamental information in guiding the development of drugs for treatment.…”

“…In rats, the bladder weight is increased one week following pBOO induction (Oka et al, 2009). At 6 weeks, the protein content and gene expression of type I and type III collagen are increased in the hypertrophic urinary bladder (Duan et al, 2015, Kim et al, 2000). In guinea pigs, the bladder weight and DNA content are not changed at one week, but are increased at 2, 4, and 8 weeks after obstruction, with transient increases in the mRNA levels of c-fos and c-Myc at 2 weeks (Karim et al, 1992).…”