Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
EMBO Mol Med. 2013 Mar;5(3):441-55. doi: 10.1002/emmm.201201475. Epub 2013 Feb 12.
ADAM17 and its inhibitor TIMP3 are involved in nephropathy, but their role in diabetic kidney disease (DKD) is unclear. Diabetic Timp3(-/-) mice showed increased albuminuria, increased membrane thickness and mesangial expansion. Microarray profiling uncovered a significant reduction of Foxo1 expression in diabetic Timp3(-/-) mice compared to WT, along with FoxO1 target genes involved in autophagy, while STAT1, a repressor of FoxO1 transcription, was increased. Re-expression of Timp3 in Timp3(-/-) mesangial cells rescued the expression of Foxo1 and its targets, and decreased STAT1 expression to control levels; abolishing STAT1 expression led to a rescue of FoxO1, evoking a role of STAT1 in linking Timp3 deficiency to FoxO1. Studies on kidney biopsies from patients with diabetic nephropathy confirmed a significant reduction in TIMP3, FoxO1 and FoxO1 target genes involved in autophagy compared to controls, while STAT1 expression was strongly increased. Our study suggests that loss of TIMP3 is a hallmark of DKD in human and mouse models and designates TIMP3 as a new possible therapeutic target for diabetic nephropathy.
ADAM17 及其抑制剂 TIMP3 参与肾病，但它们在糖尿病肾病（DKD）中的作用尚不清楚。糖尿病 Timp3（-/-）小鼠表现出白蛋白尿增加、膜厚度增加和系膜扩张。微阵列分析显示，与 WT 相比，糖尿病 Timp3（-/-）小鼠中 Foxo1 的表达显著降低，与自噬相关的 FoxO1 靶基因减少，而 STAT1（Foxo1 转录的抑制剂）增加。在 Timp3（-/-）系膜细胞中重新表达 TIMP3 可挽救 Foxo1 及其靶基因的表达，并将 STAT1 表达降低至对照水平；消除 STAT1 表达可挽救 Foxo1，表明 STAT1 在将 TIMP3 缺乏与 Foxo1 联系起来方面发挥作用。对糖尿病肾病患者肾活检组织的研究证实，与对照组相比，TIMP3、FoxO1 和自噬相关的 FoxO1 靶基因表达显著降低，而 STAT1 表达显著增加。我们的研究表明，TIMP3 的缺失是人类和小鼠模型中 DKD 的一个标志，并将 TIMP3 指定为糖尿病肾病的一个新的潜在治疗靶点。
