Min Lulin, Chen Yixin, Liu Ruijie, Li Zhengzhe, Gu Leyi, Mallipattu Sandeep, Das Bhaskar, Lee Kyung, He John Cijiang, Zhong Fang
Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Nephrology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
J Am Soc Nephrol. 2025 Feb 1;36(2):193-204. doi: 10.1681/ASN.0000000000000498. Epub 2024 Oct 9.
Krüppel-like factor 2 (KLF2) has emerged as a key endoprotective regulator by suppressing inflammatory and oxidative pathways, thrombotic activation, and angiogenesis. Our study now demonstrates that KLF2 protects against glomerular endothelial injury and attenuates diabetic kidney disease progression in mice. Compound 6 is a novel KLF2 activator that can potentially confer dual cardiorenal protection against diabetic complications.
Diabetic kidney disease (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 Krüppel-like factor 2 (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 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.
We first examined the effects of endothelial cell–specific inducible overexpression of KLF2 (KLF2) in streptozotocin-induced diabetic mice. We developed small molecule KLF2 activators and tested whether higher KLF2 activity could impede DKD progression in type 2 diabetic and BTBR mice.
Diabetic KLF2 mice had attenuated albuminuria, glomerular endothelial cell injury, and diabetic glomerulopathy compared with control diabetic mice. A novel KLF2 activator, compound 6 (C-6), effectively induced downstream expression and suppressed NF-kB activation in glomerular endothelial cells. The administration of C-6 improved albuminuria and glomerulopathy in and BTBR mice, which was associated with improved glomerular endothelial cell and podocyte injury.
These results validate KLF2 as a potential drug target and KLF2 activators, such as C-6, as a novel therapy for DKD.
Krüppel样因子2（KLF2）已成为一种关键的内源性保护调节因子，可抑制炎症和氧化途径、血栓形成激活及血管生成。我们的研究表明，KLF2可保护小鼠肾小球内皮细胞免受损伤，并减轻糖尿病肾病进展。化合物6是一种新型KLF2激活剂，可能对糖尿病并发症具有双重心肾保护作用。
糖尿病肾病（DKD）是一种微血管疾病，肾小球内皮细胞损伤是DKD发展中的关键病理事件。通过对肾小球转录组进行无偏筛选，我们之前在糖尿病肾病中发现Krüppel样因子2（KLF2）是一个高度调控的基因。KLF2通过抑制炎症、血栓形成激活及血管生成在内皮细胞中发挥保护作用，所有这些对心血管疾病都有保护作用。我们之前证明，内皮细胞特异性敲除KLF2会加剧糖尿病诱导的小鼠肾小球内皮细胞损伤和DKD。因此，在本研究中，我们试图评估在DKD小鼠模型中激活KLF2的治疗潜力。
我们首先检测了在链脲佐菌素诱导的糖尿病小鼠中内皮细胞特异性诱导过表达KLF2（KLF2）的效果。我们开发了小分子KLF2激活剂，并测试更高的KLF2活性是否能阻止2型糖尿病ob/ob和BTBR小鼠的DKD进展。
与对照糖尿病小鼠相比，糖尿病KLF2小鼠的蛋白尿、肾小球内皮细胞损伤和糖尿病肾小球病变有所减轻。一种新型KLF2激活剂化合物6（C-6）可有效诱导下游基因表达，并抑制肾小球内皮细胞中的NF-κB激活。给予C-6可改善ob/ob和BTBR小鼠的蛋白尿和肾小球病变，这与肾小球内皮细胞和足细胞损伤的改善有关。
这些结果证实KLF2是一个潜在的药物靶点，而KLF2激活剂如C-6是DKD的一种新疗法。
