Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.
Kidney Int. 2011 Jun;79(12):1312-21. doi: 10.1038/ki.2011.39. Epub 2011 Mar 9.
Clinical trials and experimental studies have highlighted the importance of epigenetic processes in the development of diabetic complications. One of the earliest features of diabetic nephropathy is renal enlargement. The epidermal growth factor (EGF) has a pivotal role in the development of diabetic nephromegaly and transactivation of its receptor has been implicated in the pathogenesis of later-stage disease. As EGF signaling is altered by the acetylation status of histone proteins, we measured the effects of the histone deacetylase (HDAC) inhibitor, vorinostat, in mediating renal enlargement in diabetes focusing on the EGF-EGF receptor (EGFR) axis. In cultured proximal tubule (normal rat kidney) cells, vorinostat treatment reduced EGFR protein and mRNA, and attenuated cellular proliferation. Within 72 h of diabetes induction with streptozotocin, urinary EGF excretion was increased approximately threefold and was unaffected by vorinostat, even though the kidneys of vorinostat-treated diabetic rats had reduced tubular epithelial cell proliferation. Daily treatment of diabetic rats with vorinostat for 4 weeks blunted renal growth and glomerular hypertrophy. Thus, early renal changes in diabetes are amenable to epigenetic intervention. Attenuating effects of HDAC inhibition, although multifactorial, are likely to be mediated in part through downregulation of the EGFR.
临床研究和实验研究强调了表观遗传过程在糖尿病并发症发展中的重要性。糖尿病肾病的最早特征之一是肾脏增大。表皮生长因子（EGF）在糖尿病肾肥大的发展中起着关键作用，其受体的转激活与疾病后期的发病机制有关。由于 EGF 信号受组蛋白蛋白乙酰化状态的改变，我们测量了组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他在介导糖尿病肾脏增大中的作用，重点关注 EGF-表皮生长因子受体（EGFR）轴。在培养的近端肾小管（正常大鼠肾）细胞中，伏立诺他处理降低了 EGFR 蛋白和 mRNA，并减弱了细胞增殖。在链脲佐菌素诱导糖尿病后 72 小时内，尿 EGF 排泄增加约三倍，伏立诺他对此没有影响，尽管伏立诺他治疗的糖尿病大鼠的肾脏肾小管上皮细胞增殖减少。4 周的糖尿病大鼠每日用伏立诺他治疗可减轻肾脏生长和肾小球肥大。因此，糖尿病的早期肾脏变化可进行表观遗传干预。尽管 HDAC 抑制的减弱作用是多因素的，但可能部分通过下调 EGFR 来介导。
