Targeting Krüppel-Like Factor 2 as a Novel Therapy for Glomerular Endothelial Cell Injury in Diabetic Kidney Disease.

Abstract

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 <i>Klf2</i> 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^ov) 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 <i>db/db</i> and BTBR <i>ob/ob</i> mice. Diabetic KLF2^ov 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 <i>Nos3</i> expression and suppressed NF-kB activation in glomerular endothelial cells. The administration of C-6 improved albuminuria and glomerulopathy in <i>db/db</i> and BTBR <i>ob/ob</i> 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.