High-fructose intake induces hypertension via the renal expression of (pro)renin receptor (PRR) that stimulates the expression of sodium/hydrogen exchanger 3, Na/K/2Cl cotransporter 2, and genes of the intrarenal renin-angiotensin system. We hypothesize that maternal high-fructose intake induces hypertension in subsequent generation offspring through activating histone codes on the PRR promoter. Mice dams were offered 20% fructose solution during pregnancy and lactation, while the subsequent 1st to 4th generation offspring were raised without fructose. Blood pressure was measured via tail-cuff method. The mRNA and protein expression were determined using quantitative real-time polymerase chain reaction and western blotting, respectively. Histone modification was evaluated using a chromatin immunoprecipitation assay. Maternal high-fructose intake statistically significantly increased blood pressure in the 1st and 2nd generations of offspring compared to the control group. Expression levels of sodium transporters and PRR were increased in the kidneys of the 1st to 3rd generation offspring. Increased enrichment of active histone codes such as H3Ac and H3K4me2 but decreased enrichment of repressive histone codes such as H3K9me3 and H3K27me3 on the PRR promoter were observed in the 1st to 3rd not the 4th generation. Moreover, there was increased the mRNA expression for histone acetyltransferase and methyl transferases for H3K4 in the 1st and 2nd generation offspring compared to the control group. This study implicates that maternal high-fructose intake induces hypertension in multigenerational offspring through activating histone codes on the PRR promoter. (C) 2020 Elsevier Inc. All rights reserved.