Zhong Fang, Chen Habing, Wei Chengguo, Zhang Weijia, Li Zhengzhe, Jain Mukesh K, Chuang Peter Y, Chen Hongyu, Wang Yongjun, Mallipattu Sandeep K, He John C
1] Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2] Department of Nephrology, Hang Zhou Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Zhejiang, China.
1] Department of Medicine/Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2] Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
Kidney Int. 2015 Feb;87(2):382-95. doi: 10.1038/ki.2014.286. Epub 2014 Sep 3.
Krüppel-like factor 2 (KLF2), a shear stress-inducible transcription factor, has endoprotective effects. In streptozotocin-induced diabetic rats, we found that glomerular Klf2 expression was reduced in comparison with nondiabetic rats. However, normalization of hyperglycemia by insulin treatment increased Klf2 expression to a level higher than that of nondiabetic rats. Consistent with this, we found that Klf2 expression was suppressed by high glucose but increased by insulin in cultured endothelial cells. To determine the role of KLF2 in streptozotocin-induced diabetic nephropathy, we used endothelial cell-specific Klf2 heterozygous knockout mice and found that diabetic knockout mice developed more kidney/glomerular hypertrophy and proteinuria than diabetic wild-type mice. Glomerular expression of Vegfa, Flk1, and angiopoietin 2 increased, but expression of Flt1, Tie2, and angiopoietin 1 decreased, in diabetic knockout mice compared with diabetic wild-type mice. Glomerular expression of ZO-1, glycocalyx, and eNOS was also decreased in diabetic knockout compared with diabetic wild-type mice. These data suggest knockdown of Klf2 expression in the endothelial cells induced more endothelial cell injury. Interestingly, podocyte injury was also more prominent in diabetic knockout compared with diabetic wild-type mice, indicating a cross talk between these two cell types. Thus, KLF2 may play a role in glomerular endothelial cell injury in early diabetic nephropathy.
Krüppel样因子2（KLF2）是一种剪切应力诱导的转录因子，具有内皮保护作用。在链脲佐菌素诱导的糖尿病大鼠中，我们发现与非糖尿病大鼠相比，肾小球Klf2表达降低。然而，胰岛素治疗使高血糖正常化后，Klf2表达增加至高于非糖尿病大鼠的水平。与此一致，我们发现在培养的内皮细胞中，高糖抑制Klf2表达，而胰岛素则使其增加。为了确定KLF2在链脲佐菌素诱导的糖尿病肾病中的作用，我们使用了内皮细胞特异性Klf2杂合敲除小鼠，发现糖尿病敲除小鼠比糖尿病野生型小鼠出现更多的肾脏/肾小球肥大和蛋白尿。与糖尿病野生型小鼠相比，糖尿病敲除小鼠中Vegfa、Flk1和血管生成素2的肾小球表达增加，但Flt1、Tie2和血管生成素1的表达降低。与糖尿病野生型小鼠相比，糖尿病敲除小鼠中ZO-1、糖萼和eNOS的肾小球表达也降低。这些数据表明，内皮细胞中Klf2表达的敲低诱导了更多的内皮细胞损伤。有趣的是，与糖尿病野生型小鼠相比，糖尿病敲除小鼠中的足细胞损伤也更明显，表明这两种细胞类型之间存在相互作用。因此，KLF2可能在早期糖尿病肾病的肾小球内皮细胞损伤中起作用。
