BACKGROUND DKD is a microvascular disease, and glomerular endothelial cell injury is a key pathological event in DKD development. Through unbiased screening of glomerular transcriptomes, we previously identified KLF2 as a highly regulated gene in diabetic kidneys. KLF2 exhibits protective effects in endothelial cells by inhibiting inflammation, thrombotic activation, and angiogenesis, all of which are protective for cardiovascular disease. We previously demonstrated that endothelial cell-specific ablation of Klf2 exacerbated diabetes-induced glomerular endothelial cell injury and DKD in mice. Therefore in this study, we sought to assess the therapeutic potential of KLF2 activation in murine models of DKD. METHODS We first examined the effects of endothelial cell-specific inducible overexpression of KLF2 (KLF2ov) in streptozotocin-induced diabetic mice. We developed small molecule KLF2 activators and tested whether increased KLF2 activity could impede DKD progression in type 2 diabetic db/db and BTBR ob/ob mice. RESULTS Diabetic KLF2ov mice had attenuated albuminuria, glomerular endothelial cell injury, and diabetic glomerulopathy compared to control diabetic mice. Novel KLF2 activator, compound 6 (C-6) effectively induced downstream Nos3 expression and suppressed NF-kB activation in glomerular endothelial cells. The administration of C-6 improved albuminuria and glomerulopathy in db/db and BTBR ob/ob mice, which was associated with improved glomerular endothelial cell and podocyte injury. CONCLUSIONS These results validate KLF2 as a potential drug target and KLF2 activators such as C-6 as a novel therapy for DKD.

中文翻译：

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靶向 KLF2 作为糖尿病肾病肾小球内皮细胞损伤的新型疗法。


背景 DKD 是一种微血管疾病，肾小球内皮细胞损伤是 DKD 发展的关键病理事件。通过对肾小球转录组的无偏倚筛选，我们之前确定 KLF2 是糖尿病肾脏中高度调控的基因。KLF2 通过抑制炎症、血栓激活和血管生成在内皮细胞中表现出保护作用，所有这些都对心血管疾病具有保护作用。我们之前证明 Klf2 的内皮细胞特异性消融加剧了糖尿病诱导的小鼠肾小球内皮细胞损伤和 DKD。因此，在这项研究中，我们试图评估 KLF2 激活在 DKD 小鼠模型中的治疗潜力。方法 我们首先检查了链脲佐菌素诱导的糖尿病小鼠内皮细胞特异性诱导过表达 KLF2 （KLF2ov） 的影响。我们开发了小分子 KLF2 激活剂，并测试了 KLF2 活性增加是否可以阻止 2 型糖尿病 db/db 和 BTBR ob/ob 小鼠的 DKD 进展。结果 与对照糖尿病小鼠相比，糖尿病 KLF2ov 小鼠的白蛋白尿、肾小球内皮细胞损伤和糖尿病肾小球病减轻。新型 KLF2 激活剂化合物 6 （C-6） 有效诱导肾小球内皮细胞下游 Nos3 表达并抑制 NF-kB 活化。C-6 的给药改善了 db/db 和 BTBR ob/ob 小鼠的白蛋白尿和肾小球病，这与改善肾小球内皮细胞和足细胞损伤有关。结论 这些结果验证了 KLF2 作为潜在的药物靶点和 KLF2 激活剂（如 C-6）作为 DKD 的新疗法。