Department of Dermatology, Foshan Hospital of Traditional Chinese Medicine, Foshan, China.
Department of Medicine and Therapeutics and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Clin Sci (Lond). 2018 Jul 9;132(13):1403-1415. doi: 10.1042/CS20180243. Print 2018 Jul 16.
It is well established that Smad3 is a key downstream effector of transforming growth factor-β (TGF-β) signaling in tissue fibrogenesis. We reported here that targetting Smad3 specifically with a Smad3 inhibitor SIS3 is able to prevent or halt the progression of renal fibrosis in a mouse model of unilateral ureteral obstructive nephropathy (UUO). We found that preventive treatment with SIS3 at the time of disease induction largely suppressed progressive renal fibrosis by inhibiting α-smooth muscle actin (α-SMA) + myofibroblast accumulation and extracellular matrix (collagen I (Col.I) and fibronectin (FN)) production. Importantly, we also found that treatment with SIS3 on established mouse model of UUO from day 4 after UUO nephropathy halted the progression of renal fibrosis. Mechanistically, the preventive and therapeutic effects of SIS3 on renal fibrosis were associated with the inactivation of Smad3 signaling and inhibition of TGF-β1 expression in the UUO kidney. In conclusion, results from the present study suggest that targetting Smad3 may be a specific and effective therapy for renal fibrosis.
众所周知，Smad3 是转化生长因子-β（TGF-β）信号在组织纤维化中的关键下游效应因子。我们在这里报道，特异性靶向 Smad3 的 Smad3 抑制剂 SIS3 能够预防或阻止单侧输尿管梗阻肾病（UUO）小鼠模型中的肾纤维化进展。我们发现，在疾病诱导时预防性使用 SIS3 通过抑制α-平滑肌肌动蛋白（α-SMA）+肌成纤维细胞积聚和细胞外基质（胶原 I（Col.I）和纤维连接蛋白（FN））的产生，在很大程度上抑制了进行性肾纤维化。重要的是，我们还发现，从 UUO 肾病后第 4 天开始，用 SIS3 治疗已建立的 UUO 小鼠模型，可阻止肾纤维化的进展。从机制上讲，SIS3 对肾纤维化的预防和治疗作用与 UUO 肾脏中 Smad3 信号的失活和 TGF-β1 表达的抑制有关。总之，本研究的结果表明，靶向 Smad3 可能是一种针对肾纤维化的特异性和有效治疗方法。
