PDZK1 regulated by miR-145-5p protects against endothelial cell apoptosis and diabetic retinopathy by targeting mitochondrial function.

Mitochondria are a focus of biomedical research because of their role in apoptosis and diabetic retinopathy (DR) initiation and progression. However, the detailed mechanisms underlying mitochondrial disorders and endothelial dysfunction during DR remain elusive. We identified PDZ domain containing 1 (PDZK1) as a key factor linking endothelial mitochondrial dysfunction and cell apoptosis during DR progression. PDZK1 was downregulated by high concentrations of glucose in human retinal capillary endothelial cells (HRCECs) and decreased in serum from patients with DR. PDZK1 knockout induced endothelial cell apoptosis and an irregular and disordered arrangement of retinal cells, aggravating DR. Moreover, PDZK1 loss impaired endothelial mitochondrial function with accumulated damaged mitochondria, decreased mitochondrial DNA (mtDNA) content, and increased reactive oxygen species (ROS) production. Mechanistically, mRNA sequencing showed that PDZK1 deficiency in endothelial cells interfered with mitochondrial function by increasing ATF4 (Activating Transcription Factor 4) expression. Further studies showed that PDZK1 was inhibited by miR-145-5p. The expression of miR-145-5p was significantly upregulated in the serum of patients with DR and HRCECs with high glucose concentration, leading to endothelial dysfunction and DR progression. Our results suggested that PDZK1 deficiency is crucial in mediating retinal endothelial cell apoptosis and is associated with mitochondrial dysfunction. PDZK1 overexpression by upstream miRNA, or its downstream molecule, ATF4, may represent novel therapeutic approaches for DR treatment.