Expression of α-Klotho Is Downregulated and Associated with Oxidative Stress in the Lens in Streptozotocin-induced Diabetic Rats

Abstract

ABSTRACT Purpose: Oxidative stress, an imbalance between the production of reactive oxygen species and antioxidant defenses, plays an important role in the pathogenesis of diabetic cataract. The lens in diabetes mellitus (DM) has been shown to exhibit impaired antioxidant defenses, but the underlying mechanisms remain poorly understood. Accumulating evidence reveals that Klotho family genes can regulate antioxidant defenses and prevent oxidative stress in multiple tissues. Here, we examined whether DM alters Klotho expression in the lens and if so, whether altered Klotho expression is associated with oxidative stress in the lens in DM. Methods: Male Wistar rats were divided into DM and control groups. DM was induced by injection of streptozotocin (STZ, 60 mg/kg ip) and control rats were injected with vehicle. Twelve weeks after DM induction, levels of α-Klotho in plasma, expression of α- and γ-Klotho, and nuclear factor erythroid 2-related factor 2 (Nrf2), and levels of antioxidants superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione (GSH) and oxidative stress marker malondialdehyde (MDA) in the lens were measured. Results: Diabetic rats had markedly higher blood glucose concentrations and lower plasma α-Klotho levels than control rats. Both α- and γ-Klotho were expressed in the lens in diabetic and control rats. The expression of α-Klotho but not γ-Klotho in the lens was downregulated in diabetic rats, which was accompanied by reduced expression of nuclear Nrf2 and levels of all antioxidants and increased levels of MDA. Moreover, expression of α-Klotho in the lens was positively correlated with expression of nuclear Nrf2 and levels of all antioxidants, but negatively correlated with levels of MDA. Conclusions: These findings suggest that DM selectively reduces α-Klotho levels in the circulation and lens, which may attenuate transcriptional activity of Nrf2 and impair antioxidant defenses in response to oxidative insults, contributing to oxidative stress and cataract formation in DM.