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논문분류	춘계학술대회 초록집
제목	Phosphodiesterase-5/5-HT2B inhibitors in combination almost completely abrogate fibrotic potential of human peritoneal fibroblasts isolated from CAPD patients
저자	Saurabh Chaturvedi, Narayan Prasad, Harshit Singh, Akhilesh Jaiswal, Vikas Agarwal
출판정보	2020; 2020(1):
키워드	Peritoneal fibrosis \| Transforming Growth Factor Beta \| Serotonin2B receptor inhibitor \| Phosphodiesterase-5 inhibitor \| Myo-fibroblasts
초록	Peritoneal fibrosis (PF) leads to ultrafiltration failure (UF) in continuous ambulatory peritoneal dialysis (CAPD) patients. Serotonin (5-HT; 5-Hydroxytryptamine) produces extracellular matrix (ECM) proteins in human peritoneal fibroblasts (HPFB) in transforming growth factor beta 1 (TGF-β1) dependent manner which activates resident fibroblasts, trans-differentiate into myo-fibroblasts (MFBs), which are characterized by increased α-smooth muscle actin (α-SMA) expression and ECM proteins production. Here we evaluate the anti-fibrotic efficacy of phosphodiesterase-5 (PDE-5) inhibitor, Sildenafil, and 5-HT2B inhibitor, SB204741, in combination on HPFB. HPFB isolated from parietal peritoneum biopsy (PB) excised during laparotomy of control (n=8)/CAPD patients (n=6), incubated overnight in dispase (2.4 U/mL)/37°C. HPFB were incubated with TGF-β1 (10 ng/ml)/1 hour, later with TGF-β1 (10 ng/ml)/[Sildenafil (10µM)+SB204741 (1µM)] for 24 hours (post-treatment strategy). In pre-treatment strategy, HPFB were pre-treated with [Sildenafil (10 µM) +SB204741 (1 µM)]/1 hour and later with only TGF-β1 (10 ng/ml)/24 hours. Similar strategies were followed for individual treatments of inhibitors. Real time qPCR for pro-fibrotic genes, COL1A1, COL1A2, ACTA2, CTGF, FN1 and anti-fibrotic genes, TIMP1, MMP2 was performed. GAPDH was housekeeping gene. Immunoblotting was performed for expression of α-SMA and type 1 collagen. The results are represented as mean±SEM. All the groups were evaluated for the level of significance by using Wilcoxon matched pairs signed rank test. Significance was set at p≤0.05. In TGF-β1 stimulated HPFB, significant up-regulation of pro-fibrotic genes expression was observed, which significantly reduced on co-culture with PDE-5 plus 5-HT2B inhibitors. Ratio of anti-fibrotic genes (MMP2/TIMP1) was restored significantly. Expression of type 1 collagen was decreased significantly. Furthermore, near complete amelioration of ACTA2 as well as α-SMA protein was observed significantly (Table 1). Dual inhibition combination of PDE-5 plus 5-HT2Binhibitors lead to near complete attenuation of conversion of resident fibroblasts to MFBs and thus may have the prospective for treatment of fibrosis of peritoneum in CAPD patients.
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