Abstract
Diabetic nephropathy is the most common cause of end stage renal disease. Previously, we reported that when challenged with streptozotocin (STZ), Klotho mutant (KL+/−) mice had higher blood glucose levels compared with wild type counterparts. Here, we explored the role of Klotho, anti‐aging protein, in a mouse model of STZ‐induced early diabetic nephropathy. Male KL+/− mice (6 to 8 weeks) were injected with multiple low doses of STZ. Urinary excretions of albumin and blood glucose levels were measured. Kidneys were collected for histological examination and molecular assays of transforming growth factor‐β1 (TGFβ1) and mammalian targets of rapamicin (mTOR) signaling. Deficiency of Klotho in KL+/− mice exacerbated STZ‐induced increases in urine albumin, blood urea nitrogen levels, expansion of mesangial matrix in glomeruli, and kidney hypertrophy, suggesting a protective role of Klotho in kidney functions and structures. Furthermore, we found that deficiency of Klotho significantly enhanced STZ‐induced TGFβ1 signaling and mTOR signaling in kidneys. These data suggested deficiency of Klotho may exacerbate diabetic nephropathy via enhancing both TGFβ1 and mTOR signaling in kidneys. Thus, Klotho gene or protein delivery may have therapeutic potential for early diabetic nephropathy.
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