PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells.

Abstract

Diabetic retinopathy (DR) is a neurovascular complication of diabetes. As a crucial player in the retinal physiology, Müller cells are affected in DR, impairments of Müller cell function lead to retinal malfunctions. Therefore, searching for approaches to mitigate diabetes-induced injury in Müller cells is imperative for delaying DR. Peroxiredoxin 4 (PRDX4), an important endoplasmic reticulum (ER)-resident antioxidant, was explored in this study for its potential protective role against DR. Streptozotocin (STZ)-induced mouse model of diabetes and high glucose (HG)-induced Müller cells were utilized to assess the impact of PRDX4. Compared to wild-type mice, PRDX4 knockout exacerbated retinal neurodegeneration, reactive gliosis, cell apoptosis, endoplasmic reticulum (ER) stress, oxidative stress, and mitochondrial dysfunction in diabetic retinas. Knockdown of PRDX4 aggravated high glucose (HG)-induced reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells. Conversely, PRDX4 overexpression in Müller cells protected against HG-induced cell damage. Mechanistically, PRDX4 promoted the degradation of DPP4, which is associated with DR in type 1 diabetics, thereby alleviating HG-stimulated Müller cell abnormalities. Our study indicated that PRDX4 is a crucial protective regulator in DR progression via destabilization of DPP4 protein and suggested enhancement of PRDX4 level may represent a promising approach for treating DR.