KLF2 is a novel endoprotective target for DKD

Summary Patients with diabetic kidney disease (DKD) frequently develop cardiovascular disease (CVD), and vascular complications and endothelial cell injury is a common pathological event for both DKD and CVD. Therefore, the development of novel treatments with dual cardio-renal protection is urgently needed. Krüppel-like factors (KLFs) are a subfamily of 17 DNA-binding transcriptional regulators. Through unbiased screening, we identified KLF2 as a highly regulated gene in the diabetic kidney. KLF2 is known to mediate flow-dependent phenotype in endothelial cells, and confers endoprotective effects by inhibition of pro-inflammatory pathways, thrombotic activation, and uncontrolled angiogenesis. Due to these endo-protective effects, KLF2 has been shown to be protective in CVD. Over the last several years, we have generated interesting data to support the critical role of KLF2 in protecting GEC injury in DKD. We find: 1) KLF2 expression is regulated by many factors in GECs such as glomerular hyperfiltration, high glucose, TGF-α, sex hormone, and SGLT2i. 2) KLF2 expression is reduced in GECs of human diabetic kidneys and reduction of KLF2 expression is associated with the progression of human DKD. Two missense mutations of hKLF2 gene were found to be associated with ESKD. 3) KLF2 has anti-inflammatory effects and regulates eNOS expression in GECs. 4) Endothelial cell-specific KLF2 KO mice with diabetes develop more severe GEC injury and DKD, while endothelial cell-specific overexpression of KLF2 has protective effects in DKD mice. 5) KO of KLF2 in endothelial cells also aggravates proteinuria and renal dysfunction in the mice with unilateral nephrectomy. Based on these preliminary data, we hypothesized that KLF2 has a major protective role against GEC injury in DKD and KLF2 could be an attractive drug target for treatment of DKD. To further test this hypothesis, we propose the following three aims: Aim 1: Determine how KLF2 is regulated in diabetic conditions. Aim 2: Determine how KLF2 protects against GEC injury and progression of DKD. Aim 3: Determine whether KLF2 agonists could be developed as a novel drug for the treatment of DKD. These studies will help us to further explore the mechanisms of the endo-protective role of KLF2, validate KLF2 as a potential drug target, and develop KLF2 agonists as a potential treatment for DKD. We believe that KLF2 agonists could be eventually developed as a novel drug for cardio-renal protection in diabetic patients with CKD/CVD.