Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California, Veterans Administration San Diego HealthCare System, La Jolla, 92093, USA.
Am J Physiol Renal Physiol. 2011 Aug;301(2):F271-9. doi: 10.1152/ajprenal.00221.2011. Epub 2011 May 4.
The predominant transcription factors regulating key genes in diabetic kidney disease have not been established. The transcription factor upstream stimulatory factor 1 (USF1) is an important regulator of glucose-mediated transforming growth factor (TGF)-β1 expression in mesangial cells; however, its role in the development of diabetic kidney disease has not been evaluated. In the present study, wild-type (WT; USF1 +/+), heterozygous (USF1 +/-), and homozygous (USF1 -/-) knockout mice were intercrossed with Akita mice (Ins2/Akita) to induce type 1 diabetes. Mice were studied up to 36 wk of age. The degree of hyperglycemia and kidney hypertrophy were similar in all groups of diabetic mice; however, the USF1 -/- diabetic mice had significantly less albuminuria and mesangial matrix expansion than the WT diabetic mice. TGF-β1 and renin gene expression and protein were substantially increased in the WT diabetic mice but not in USF1 -/- diabetic mice. The underlying pathway by which USF1 is regulated by high glucose was investigated in mesangial cell culture. High glucose inhibited AMP-activated protein kinase (AMPK) activity and increased USF1 nuclear translocation. Activation of AMPK with AICAR stimulated AMPK activity and reduced nuclear accumulation of USF1. We thus conclude that USF1 is a critical transcription factor regulating diabetic kidney disease and plays a critical role in albuminuria, mesangial matrix accumulation, and TGF-β1 and renin stimulation in diabetic kidney disease. AMPK activity may play a key role in high glucose-induced regulation of USF1.
调控糖尿病肾病关键基因的主要转录因子尚未确定。转录因子上游刺激因子 1（USF1）是调节系膜细胞葡萄糖介导的转化生长因子（TGF）-β1表达的重要调节因子；然而，其在糖尿病肾病发展中的作用尚未得到评估。在本研究中，野生型（WT；USF1 + / +）、杂合型（USF1 +/-）和纯合型（USF1 -/-）敲除小鼠与 Akita 小鼠（Ins2 / Akita）杂交以诱导 1 型糖尿病。研究持续至 36 周龄。所有糖尿病小鼠的高血糖和肾脏肥大程度相似；然而，USF1 -/-糖尿病小鼠的白蛋白尿和系膜基质扩张程度明显低于 WT 糖尿病小鼠。WT 糖尿病小鼠的 TGF-β1 和肾素基因表达和蛋白显著增加，但 USF1 -/-糖尿病小鼠则没有。在系膜细胞培养中研究了 USF1 被高葡萄糖调节的潜在途径。高葡萄糖抑制 AMP 激活蛋白激酶（AMPK）活性并增加 USF1 核易位。用 AICAR 激活 AMPK 可刺激 AMPK 活性并减少 USF1 的核积累。因此，我们得出结论，USF1 是调节糖尿病肾病的关键转录因子，在糖尿病肾病中的白蛋白尿、系膜基质积累以及 TGF-β1 和肾素刺激中发挥关键作用。AMPK 活性可能在高葡萄糖诱导的 USF1 调节中发挥关键作用。
