Knockdown of Krüppel-Like Factor 9 Inhibits Aberrant Retinal Angiogenesis and Mitigates Proliferative Diabetic Retinopathy.

Abstract

Advanced proliferative diabetic retinopathy (PDR) characterized by aberrant retinal angiogenesis is a leading cause of retinal detachment and blindness. Krüppel-like factor 9 (KLF9), a member of the zinc-finger family of transcription factors, participates in the development of diabetic nephropathy and the promotion of angiogenesis of human umbilical vein endothelial cells. Therefore, we speculate that KLF9 may exert a crucial role in PDR. The current study revealed that KLF9 was highly expressed in the high glucose (HG)-treated human retinal microvascular endothelial cells (HRMECs) and the retinas of oxygen-induced retinopathy (OIR) rats. Knockdown of KLF9 inhibited the proliferation, migratory capability, invasiveness and tube formation of HG-treated HRMECs. Besides, knockdown of KLF9 decreased the expression of yes-associated protein 1 (YAP1) in HG-treated HRMECs. Dual-luciferase reporter assays confirmed that KLF9 transcriptionally upregulated YAP1 expression. Overexpression of YAP1 reversed the KLF9 silencing-induced repression of HRMEC proliferation and tube formation. Further in vivo evidence demonstrated that knockdown of KLF9 reduced the expression of Ki67, CD31 and vascular endothelial growth factor A (VEGFA) in the retinas of OIR rats. Collectively, KLF9 silencing might mitigate the progression of PDR by inhibiting angiogenesis via blocking YAP1 transcription.