DJ-1 regulates the expression of renal (pro)renin receptor via reactive oxygen species-mediated epigenetic modification

Background: DJ-1 protein plays multifunctional roles including transcriptional regulation and scavenging oxidative stress: thus, it may be associated with the development of renal disorders. We investigated whether DJ-1 protein regulates the expression of (pro)renin receptor (PRR), a newly identified member of renin-angiotensin system. Methods: The levels of mRNA and protein were determined by real-time PCR and western blot, respectively. H2O2 production was tested by using fluorescence probe. Histone modification was determined by chromatin immunoprecipitation. Results: The expression of PRR was significantly higher in the kidney from DJ-1 knockout mice (DJ-1(-/-)) compared with wild-type mice (DJ-1(+/+)). Histone deacetylase 1 recruitment at the PRR promoter was lower, and histone H3 acetylation and RNA polymerase II recruitment were higher in DJ-1(-/-) than in DJ-1(+/+). Knockdown or inhibition of histone deacetylase 1 restored PRR expression in mesangial cells from DJ-1(+/+). H2O2 production was greater in DJ-1(-/-) cells compared with DJ-1(+/+) cells. These changes in PRR expression and epigenetic modification in DJ-1(-/-) cells were induced by H2O2 treatment and reversed completely by addition of an antioxidant reagent Prorenin-stimulated ERK1/2 phosphorylation was greater in DJ-1(-/-) than in DJ-1(+/+) cells and this was inhibited by a PRR-inhibitory peptide, and by AT1 and AT2 receptor inhibitors. The expression of renal fibrotic genes was higher in DJ-1(-/-) than in DJ-1(+/+) cells and decreased in PRR-knockdown DJ-1(-/-) cells. Conclusions: We conclude that DJ-1 protein regulates the expression of renal PRR through H2O2-mediated epigenetic modification. General significance: We suggest that renal DJ-1 protein may be an important molecule in the acceleration of renal pathogenesis through PRR regulation. (C) 2014 Elsevier B.V. All rights reserved.