Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Kidney Int. 2011 Dec;80(11):1159-1169. doi: 10.1038/ki.2011.255. Epub 2011 Aug 10.
Transforming growth factor-β1 (TGF-β1) upregulation occurs in virtually all chronic kidney diseases and is associated with podocyte injury and proteinuria; however, the mechanisms contributing to this in vivo are ambiguous. In vitro, incubation of podocytes with TGF-β1 induced Wnt1 expression, β-catenin activation, and stimulated the expression of Wnt/β-catenin downstream target genes. Ectopic expression of Wnt1 or β-catenin mimicked TGF-β1, induced Snail1, and suppressed nephrin expression. The Wnt antagonist, Dickkopf-1, blocked TGF-β1-induced β-catenin activation, Snail1 induction, and nephrin suppression. In vivo, ectopic expression of TGF-β1 induced Wnt1 expression, activated β-catenin, and upregulated Wnt target genes such as Snail1, MMP-7, MMP-9, desmin, Fsp1, and PAI-1 in mouse glomeruli, leading to podocyte injury and albuminuria. Consistently, concomitant expression of Dickkopf-1 gene abolished β-catenin activation, inhibited TGF-β1-triggered Wnt target gene expression, and mitigated albuminuria. Thus, canonical Wnt/β-catenin signaling mediates TGF-β1-driven podocyte injury and proteinuria. These studies suggest that Wnt/β-catenin signaling may be exploited as a therapeutic target for the treatment of proteinuric kidney diseases.
转化生长因子-β1（TGF-β1）在几乎所有慢性肾脏病中均上调，与足细胞损伤和蛋白尿有关；然而，体内导致这种情况的机制尚不清楚。在体外，将足细胞与 TGF-β1 孵育会诱导 Wnt1 表达、β-连环蛋白激活，并刺激 Wnt/β-连环蛋白下游靶基因的表达。Wnt1 或 β-连环蛋白的异位表达模拟了 TGF-β1，诱导了 Snail1，并抑制了 Nephrin 的表达。Wnt 拮抗剂 Dickkopf-1 阻断了 TGF-β1 诱导的 β-连环蛋白激活、Snail1 诱导和 Nephrin 抑制。在体内，TGF-β1 的异位表达诱导了 Wnt1 的表达，激活了 β-连环蛋白，并上调了 Wnt 靶基因，如 Snail1、MMP-7、MMP-9、desmin、Fsp1 和 PAI-1，导致足细胞损伤和白蛋白尿。一致地，Dickkopf-1 基因的同时表达消除了 β-连环蛋白的激活，抑制了 TGF-β1 触发的 Wnt 靶基因表达，并减轻了白蛋白尿。因此，经典 Wnt/β-连环蛋白信号转导介导了 TGF-β1 驱动的足细胞损伤和蛋白尿。这些研究表明，Wnt/β-连环蛋白信号可能被用作治疗蛋白尿性肾病的治疗靶点。
