Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
Department of Nephrology and Kidney Research Center, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taoyuan, Taiwan.
Biochim Biophys Acta Mol Cell Res. 2024 Jan;1871(1):119594. doi: 10.1016/j.bbamcr.2023.119594. Epub 2023 Sep 18.
Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis.
肾纤维化是导致各种形式慢性肾脏病进行性肾功能丧失的共同途径。许多致纤维化因素调节肾纤维化；两个关键因素是损伤后炎症和转化生长因子-β1（TGF-β1）诱导的肌成纤维细胞分化。肌成纤维细胞分化受微管聚合的紧密调节。北美黄连碱，一种镇咳植物生物碱，是一种先前被确定为潜在抗癌化合物的强效微管干扰剂。在这里，我们研究了北美黄连碱如何影响体外肾成纤维细胞模型和体内单侧输尿管梗阻（UUO）模型中的肾纤维化。UUO 小鼠在 UUO 手术前 1 天腹腔内给予北美黄连碱，并在术后每天给予。手术后 7 天，收集肾脏进行进一步分析。为了分析北美黄连碱是否抑制下游 TGF-β1 相关信号，我们先用北美黄连碱孵育 NRK-49F 成纤维细胞，然后进行 TGF-β1 刺激。在 UUO 小鼠中，北美黄连碱通过降低 TLR2 表达、调节 NLRP3 炎性小体激活、减少巨噬细胞浸润和拮抗 M2 巨噬细胞表型来减轻细胞外基质蛋白沉积和 I 型胶原、IV 型胶原、α-平滑肌肌动蛋白和纤维连接蛋白的表达水平。此外，北美黄连碱通过下调 TGF-β/Smads 信号通路抑制 TGF-β1 诱导的成纤维细胞-肌成纤维细胞转化，减少 UUO 肾脏中的肾小管间质炎症。这些结果表明，北美黄连碱可减少 UUO 小鼠肾脏中的肾小管间质炎症和纤维化，并抑制 TGF-β1 诱导的成纤维细胞-肌成纤维细胞转化。北美黄连碱是一种非处方镇咳药，已安全使用数十年。因此，北美黄连碱是抑制肾肾小管间质纤维化的有吸引力的治疗剂。
