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Objective(s): The aim of this study was to observe the impact of sirolimus on proteinuria in streptozotocin (STZ) induced diabetic rats. Materials and Methods: Rats were given a single injection of STZ to induce diabetic rat model. Rats’ 24 hr urine was collected to test, urinary and the kidney tissues were harvested at the 8th and 20th weeks, respectively. Podocyte morphological changes were examined by electron microscopy and the ZO-1, podocin expressions in kidneys were detected by immunohistochemistry; the protein levels of Raptor and pS6 were measured by Western blot assay. Results: In the early stage of diabetic nephropathy (DN), sirolimus reduced the proteinuria significantly (P