BackgroundPeritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats.MethodsTo mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 μg/Kg, IP). Animals were followed up for 30 days.ResultsCG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFβ/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression.ConclusionsIn conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process.

中文翻译：

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他莫昔芬和骨形态发生蛋白-7 调节尿毒症大鼠腹膜纤维化模型中的纤维化和炎症

背景腹膜纤维化 (PF) 是腹膜透析 (PD) 的长期并发症，会影响腹膜 (PM) 的完整性和功能。了解尿毒症环境中 PF 发展的潜在机制，旨在治疗这一过程的替代治疗策略是非常有趣的。本研究的目的是分析他莫昔芬 (TAM) 和重组 BMP7 (rBMP7) 在尿毒症大鼠 PF 实验模型中的作用。通过 PF 和 CKD 的组合与严重的尿毒症，在 Wistar 大鼠中产生。PF 由腹腔 (IP) 注射葡萄糖酸氯己定 (CG) 诱导，CKD 由富含腺嘌呤的饮食诱导。尿毒症确诊为重度高血压，血尿素氮 (BUN> 120 mg/dL) 和血清肌酐水平 (> 2 mg/dL) 增加。患有 PF 的尿毒症大鼠用 TAM（10 mg/Kg 灌胃）或 BMP7（30 μg/Kg，IP）治疗。动物随访30天。结果在尿毒症大鼠中施用CG引起PM厚度、新血管生成的显着增加，表现为毛细血管密度增加和超滤能力失败。这些形态和功能变化被 TAM 或 rBMP7 处理阻止。同时，TAM 和 rBMP7 通过减少 α-SMA、细胞外基质蛋白和 TGF-β 表达显着改善 PM 纤维化反应。TAM 或 rBMP7 给药显着抑制 PF 尿毒症大鼠腹膜 Smad3 表达，阻止 Smad3 磷酸化，并诱导 Smad7 显着上调，TGFβ/Smad 信号传导的细胞内抑制剂，有助于对促纤维化基因的负调节。这两种治疗方法也能有效减少局部炎症，可能是通过上调 PF 尿毒症大鼠 PM 中 IκB-α 的表达。使用 TGF-ß 激活的原代腹膜成纤维细胞进行的体外实验证实了 TAM 或 rBMP7 在阻断炎症介质（如 IL-1ß 表达）方面的能力。结论总而言之，这些发现表明 TGF-ß/Smad 信号在 PF 中的重要作用尿毒症，提供有关使用 TAM 或 rBMP7 阻断这一过程的潜在治疗方法的数据。可能通过上调 PF 尿毒症大鼠 PM 中 IκB-α 的表达。使用 TGF-ß 激活的原代腹膜成纤维细胞进行的体外实验证实了 TAM 或 rBMP7 在阻断炎症介质（如 IL-1ß 表达）方面的能力。结论总而言之，这些发现表明 TGF-ß/Smad 信号在 PF 中的重要作用尿毒症，提供有关使用 TAM 或 rBMP7 阻断这一过程的潜在治疗方法的数据。可能通过上调 PF 尿毒症大鼠 PM 中 IκB-α 的表达。使用 TGF-ß 激活的原代腹膜成纤维细胞进行的体外实验证实了 TAM 或 rBMP7 在阻断炎症介质（如 IL-1ß 表达）方面的能力。结论总而言之，这些发现表明 TGF-ß/Smad 信号在 PF 中的重要作用尿毒症，提供有关使用 TAM 或 rBMP7 阻断这一过程的潜在治疗方法的数据。