Background: DJ-1 is critical for the mitochondrial function associated with autosomal dominant polycystic kidney disease (ADPKD). We aimed to investigate DJ-1's function in the pathogenesis of ADPKD. Methods: DJ-1 was knocked-down in IMCD3 cells to evaluate the effects of DJ-1 on cell phenotype and mitochondrial function in vitro. Furthermore, we generated three groups of mice with different expression levels of DJ-1 within an established ADPK I) model: ADPKD, ADPK(pcDNA), and ADPKD(pcDNA-DJ-1). Results: DJ-1 knock-down significantly increased oxidative stress as well as the proliferation and apoptosis rate of IMCD3 cells, along with Bd-2 down-regulation and the up-regulation of Ki67, PCNA, Bax, cleaved caspase-3, and cleaved caspase-9. DJ-1 knock-down suppressed the cellular respiration, Ca2+ absorption, and mitochondrial complex I activity in mitochondria. In vivo, we verified that DJ-1 was down-regulated in ADPKD models, and its overexpression attenuated the renal dysfunction in ADPKD models. The transgenic mice had a significantly smaller renal cyst and less interstitial fibrosis than control, accompanied bya-SMA, fibronectin, and TGF-beta 1 up-regulation. Moreover, in vivo results confirmed DJ-1 overexpression inhibited the proliferation and apoptosis of tubular epithelial cells along with down-regulation of Ki67, PCNA, p53, intracellular Cyt c, cleaved caspase-3, and cleaved caspase-9 and the up-regulation of BcI-2. Conclusions: DJ-1 was down-regulated in ADPKD models, and its overexpression may attenuate the renal dysfunction and pathological damage by regulating the proliferation, apoptosis, oxidative stress and mitochondrial metabolism, which may be mediated by the p53 signaling pathway.