Han Weixia, Wang Chen, Yang Zhifen, Mu Lin, Wu Ming, Chen Nan, Du Chunyang, Duan Huijun, Shi Yonghong
W Han, Department of Pathology, Hebei Medical University, Shijiazhuang City, China.
C Wang, Department of Pathology, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China.
J Endocrinol. 2019 Feb 1. doi: 10.1530/JOE-18-0536.
Renal fibrosis is a major pathological characteristic of diabetic nephropathy (DN). Reportedly, increased SIRT1 expression played a renal protective role in animal models of DN. This study was designed to elucidate the molecular mechanisms underlying the protective effects of SRT1720, an SIRT1 activator, against diabetes-induced renal fibrosis. Type 2 diabetic mice (db/db) were treated with SRT1720 (50 mg/kg/d) by gavage for 10 weeks. Renal proximal tubular epithelial cells (HK-2 cells) were treated with high glucose (HG, 30 mM) in the presence or absence of SRT1720 (2.5 µM) for 48 h. We observed that impaired SIRT1 expression and activity were restored by SRT1720 administration in db/db mice as well as in HG-treated HK-2 cells. Moreover, SRT1720 administration improved renal function, attenuated glomerular hypertrophy, mesangial expansion, glomerulosclerosis and interstitial fibrosis, and inhibited TGFB1 and CTGF expressions and nuclear factor κB (NF-κB) activation in db/db mice. Similarly, HG-induced epithelial-to-mesenchymal transformation (EMT), and collagen IV and fibronectin expressions were inhibited in SRT1720 treated HK-2 cells. Mechanistic studies demonstrated that SRT1720 suppressed HIF1α, GLUT1 and SNAIL expressions both in vivo and in vitro. Furthermore, Hif1α or Glut1 knockdown effectively abrogated HG-induced EMT and collagen IV and fibronectin expressions in HK-2 cells. These findings suggest that SRT1720 prevented diabetes-induced renal fibrosis via the SIRT1/HIF1α/GLUT1/SNAIL pathway.
肾纤维化是糖尿病肾病（DN）的主要病理特征。据报道，在DN动物模型中，SIRT1表达增加发挥了肾脏保护作用。本研究旨在阐明SIRT1激活剂SRT1720对糖尿病诱导的肾纤维化的保护作用的分子机制。对2型糖尿病小鼠（db/db）通过灌胃给予SRT1720（50mg/kg/d），持续10周。在存在或不存在SRT1720（2.5μM）的情况下，用高糖（HG，30mM）处理肾近端小管上皮细胞（HK-2细胞）48小时。我们观察到，在db/db小鼠以及HG处理的HK-2细胞中，给予SRT1720可恢复受损的SIRT1表达和活性。此外，给予SRT1720可改善db/db小鼠的肾功能，减轻肾小球肥大、系膜扩张、肾小球硬化和间质纤维化，并抑制TGFB1和CTGF表达以及核因子κB（NF-κB）激活。同样，在SRT1720处理的HK-2细胞中，HG诱导的上皮-间质转化（EMT）以及IV型胶原和纤连蛋白表达受到抑制。机制研究表明，SRT1720在体内和体外均抑制HIF1α、GLUT1和SNAIL表达。此外，敲低Hif1α或Glut1可有效消除HG诱导的HK-2细胞中的EMT以及IV型胶原和纤连蛋白表达。这些发现表明，SRT1720通过SIRT1/HIF1α/GLUT1/SNAIL途径预防糖尿病诱导的肾纤维化。
