Emerging functional crosstalk between the glutaredoxin system and Nrf2 antioxidant pathway: evidence from ultraviolet radiation-induced cataract formation

Purpose: To determine the function of glutaredoxin (Grx) system, both glutaredoxin 1 (Grx1) and glutaredoxin 2 (Grx2), in protecting the lens against ultraviolet (UV)-induced cataract formation by using Grx1/Grx2 double knockout (DKO) mice as a model. Methods: One-month old Grx1/Grx2 DKO and age-matched wild-type (WT) mice were exposed to UV radiation to induce cataracts. Mice were euthanized at 4 days post-exposure. The degree of the cataract and lens morphology were evaluated under a dissecting microscope. Glutathione (GSH), free protein thiol(PSH), and protein glutathionylation (PSSG) levels were measured as general markers of oxidative damage. Nrf2 and its downstream target proteins were examined using Western blot. Results: We found that UV radiation caused more severe anterior subcapsular cataract in Grx1/Grx2 DKO than that of WT mice. The opacity of the lenses in DKO mice appeared to extend deeper into the cortical and even nuclear regions. Lenses of Grx1/Grx2 DKO mice contained significant lower levels of GSH and PSH. On the other hand, the accumulation of PSSG was much higher in Grx1/Grx2 DKO group. Deletion of Grx1 and Grx2 also decreased the expression of antioxidant enzyme transcription factor regulator, Nrf2, and its downstream antioxidant genes, including catalase, superoxide dismutase (SOD), and another redox regulator of thioredoxin (Trx). These changes were especially extensive in the lens after UV exposure. Conclusions: With combined Grx1 and Grx2 deletion, the Nrf2-dependent antioxidant response is severely impaired, causing elevation of oxidative stress that may increase the lens susceptibility to UV-induced damage.