Our findings showed that melatonin treatment significantly up‐regulated the level of PTEN and Spry1 protein expression in renal fibroblasts response to TGF‐β1 induction and kidneys of UUO mice, indicating that PTEN and Spry1 protein may participate in the effects of melatonin on renal fibroblast transdifferentiation and renal fibrosis. The gene discussed is PTEN; the disease is renal fibrosis.