Activation of megakaryocytic leukemia 1 in endothelial cells contributes to diabetic retinopathy in mice

Abstract

Aims

Diabetic retinopathy (DR) represents one of the most devastating sequences in patients with diabetes. Endothelial dysfunction is a key pathological feature of and contributing factor to DR. In the present study we investigated the role of megakaryocytic leukemia 1 (MKL1) in DR pathogenesis.

Methods and materials

DR was induced in mice by feeding with a high-fat diet (HFD). The Mkl1-Rosa26-KI mice were crossed to the Cdh5-Cre^ERT2 mice to generate endothelial-specific MKL1 knock-in mice (MKL1^EC-KI).

Key findings

In cultured human primary retinal endothelial cells exposure to high glucose promoted nuclear translocation of MKL1 without altering its mRNA or protein expression. MKL1 knockdown ameliorated whereas MKL1 over-expression exacerbated high glucose induced impairment of endothelial barrier function. Compared to wild type littermates, MKL1^EC-KI mice fed on HFD displayed worsened insulin resistance and accelerated DR pathogenesis. Consistently, administration of an MKL1 inhibitor CCG-1423 protected the mice from HFD feeding induced metabolic disorders and DR pathogenesis.

Significance

Our data demonstrate that MKL1 may contribute to diabetic retinopathy by regulating endothelial behavior. Targeting MKL1 with small-molecule inhibitors can be considered as a therapeutic solution for the treatment of diabetic retinopathy.