Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, People's Republic of China.
Mol Cell Biochem. 2010 Jun;339(1-2):263-70. doi: 10.1007/s11010-010-0389-6. Epub 2010 Feb 16.
The epithelial to mesenchymal transition (EMT) is a crucial event for renal fibrosis that can be elicited by TGF-beta1/Smads signaling and its downstream mediator connective tissue growth factor (CTGF). As a distinct member of the TGF-beta superfamily, Lefty A has been shown to be significantly downregulated in the kidneys of patients with severe ureteral obstruction, suggesting its role in renal fibrosis induced by obstructive nephropathy. In order to determine whether Lefty A prevents TGF-beta1-induced EMT, human proximal tubule epithelial cells (HK-2) were stably transfected with Lefty A or control vectors and stimulated with 10 ng/ml TGF-beta1 for 48 h. The results show that stimulation with TGF-beta1 led to EMT including cell morphology changes, Smad2/3 signaling pathway activation, increased alpha-SMA, collagen type I, and CTGF expression, and decreased E-cadherin expression in mock-transfected HK-2 cells. Overexpression of Lefty A efficiently blocked p-Smad2/3 activation and attenuated all these EMT changes induced by TGF-beta1. This finding suggests that Lefty A may serve as a potential new therapeutic target to inhibit or even reverse EMT during the process of renal fibrosis.
上皮间质转化（EMT）是肾脏纤维化的关键事件，可被 TGF-β1/Smads 信号及其下游介质结缔组织生长因子（CTGF）诱导。Lefty A 作为 TGF-β 超家族的一个独特成员，已被证明在严重输尿管梗阻患者的肾脏中显著下调，提示其在梗阻性肾病引起的肾脏纤维化中发挥作用。为了确定 Lefty A 是否可预防 TGF-β1 诱导的 EMT，我们将 Lefty A 或对照载体稳定转染入人近端肾小管上皮细胞（HK-2），并用 10ng/ml TGF-β1 刺激 48 小时。结果表明，TGF-β1 刺激导致 EMT，包括细胞形态改变、Smad2/3 信号通路激活、α-SMA、胶原 I 和 CTGF 表达增加，以及 E-钙黏蛋白表达减少。Lefty A 的过表达有效地阻断了 p-Smad2/3 的激活，并减弱了 TGF-β1 诱导的所有这些 EMT 变化。这一发现表明，Lefty A 可能成为一种潜在的新的治疗靶点，以抑制甚至逆转肾脏纤维化过程中的 EMT。
