Megakaryocytic Leukemia 1(MKL1)Mediates High Glucose Induced Epithelial-mesenchymal Transition By Activating LOX Transcription

Diabetic retinopathy(DR)is one of the most common and devastating complications of diabetes mellitus,affecting in approximately one-third of patients with diabetes mellitus.It is the important reason of visual impairment in the working-age population and the elderly population.The progress and deterioration of diabetic retinopathy are closely related to the long-term course of diabetes mellitus and the poor control of blood sugar and other risk factors.When exposed to high glucose(HG),retinal pigment epithelial cells undergo profound alterations both morphologically and functionally in a well-conserved process known as epithelial-to-mesenchymal transition(EMT).The mechanism governing HG-induced EMT in retinal pigment epithelial cells is not completely understood.Here we report that treatment with 25 m M glucose led to EMT in retinal pigmented epithelial cells(RPE)characterized by a simultaneous down-regulation of E-Cadherin(encoded by CDH1)and up-regulation of alpha smooth muscle actin(encoded by ACTA2).HG-induced EMT in RPEs was accompanied by augmented expression and enhanced nuclear enrichment of MKL1.Megakaryocytic leukemia1(MKL1),is a transcriptional modulator,is also called as myeloid acute leukemia(MAL)or myocardin-related transcription factor A(MRTF-A).In contrast,MKL1 knockdown by si RNA or inhibition by CCG-1423 abrogated HG-induced EMT in RPEs.Of interest,MKL1 mediated the transcriptional activation of LOX,a mesenchymal marker,in RPEs in response to HG stimulation.Mechanistically,MKL1 interacted with and was recruited by AP-1 to the proximal LOX promoter to promote LOX trans-activation likely through altering the chromatin structure.Finally,LOX depletion by si RNA or inhibition by aminopropionitrile in RPEs abolished HG-induced EMT.In conclusion,our data support a role for MKL1 in mediating HG-induced EMT in retinal epithelial cells via epigenetic activation of LOX transcription.