Downregulation of klotho gene expression in streptozotocin-induced diabetic rats

Objective: The expression of klotho, which may function as an anti-aging hormone, is most abundant in the kidney. We have investigated the regulation of klotho expression in the kidneys of diabetic rats. Methods: Diabetes was induced by a single i.v. injection of streptozotocin (STZ) at a dose of 60 mg/kg. Renal klotho expression was investigated 8 weeks post-STZ injection. Some rats were given losartan or deferoxamine from S weeks post-STZ injection until sacrifice. Klotho expression was examined by Western blot analysis and quantitative reverse transcription-polymerase chain reaction. Results: Expression of Klotho protein was reduced by approximately a third in the kidneys of diabetic rats compared to that of the untreated control rats. This downregulation was suppressed by either losartan or deferoxamine; these drugs also decreased the albuminuria. Histological study showed that, in the kidneys of the STZ-induced diabetic rats, mRNA expression of klotho, albeit less intense than in the untreated control, was observed in the tubular epithelial cells, and was co-localized with heme oxygenase-1, an oxidative stress-sensitive gene. Conclusion: Expression of klotho was downregulated in the kidneys of diabetic rats. An activation of the renin-angiotensin system, altered iron homeostasis, and presumably enhanced oxidative stress, may play a role in this phenomenon.