Klotho ameliorates the onset and progression of cataract via suppressing oxidative stress and inflammation in the lens in streptozotocin-induced diabetic rats

Increased oxidative stress and inflammation play an important role in the pathogenesis of diabetic cataract. Klotho, known as an anti-ageing protein, has antioxidative and anti-inflammatory properties. Klotho is expressed in limited tissues including the lens. Here we examined whether klotho expression is decreased in diabetic lens and, if so, whether klotho treatment can prevent diabetic cataract formation. Streptozotocin (STZ)-induced diabetic rats and age-matched control rats were treated with vehicle or klotho protein, starting at 1 week after STZ injection. Twelve weeks after treatment, cataract formation was observed in diabetic rats but not control rats. Cataract formation and scores were significantly less in klotho-treated diabetic rats than vehicle-treated diabetic rats. Levels of klotho in plasma, aqueous humor and lens were significantly decreased in vehicle-treated diabetic rats, compared with control rats, but were restored in klotho-treated diabetic rats. Additionally, vehicle-treated diabetic rats had increased oxidative stress and inflammation in the lens, which were associated with decreased antioxidant transcriptional master regulator Nrf2 activity and increased transcription factor NF-κB activity. All of these findings were ameliorated in klotho-treated diabetic rats. Notably, klotho treatment did not alter blood glucose in diabetic rats. These results indicate that klotho reduction may increase susceptibility of the lens to oxidative and inflammatory insults, promoting cataract formation under diabetic conditions. Klotho treatment can ameliorate the onset and progression of diabetic cataract via enhancing Nrf2-mediated antioxidant defense and suppressing NF-κB-mediated inflammatory responses. Klotho in the lens may be a novel therapeutic target for prevention of cataract formation in diabetes.