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Obesity and related disorders have increased concurrently with an increased consumption of saturated fatty acids. We examined whether post-weaning high fat (HF) diet would exacerbate offspring vulnerability to maternal HF-induced programmed hypertension and kidney disease sex-specifically, with a focus on the kidney. Next, we aimed to elucidate the gene–diet interactions that contribute to maternal HF-induced renal programming using the next generation RNA sequencing (NGS) technology. Female Sprague-Dawley rats received either a normal diet (ND) or HF diet (D12331, Research Diets) for five weeks before the delivery. The offspring of both sexes were put on either the ND or HF diet from weaning to six months of age, resulting in four groups of each sex (maternal diet/post-weaning diet; n = 5–7/group): ND/ND, ND/HF, HF/ND, and HF/HF. Post-weaning HF diet increased bodyweights of both ND/HF and HF/HF animals from three to six months only in males. Post-weaning HF diet increased systolic blood pressure in male and female offspring, irrespective of whether they were exposed to maternal HF or not. Male HF/HF offspring showed greater degrees of glomerular and tubular injury compared to the ND/ND group. Our NGS data showed that maternal HF diet significantly altered renal transcriptome with female offspring being more HF-sensitive. HF diet induced hypertension and renal injury are associated with oxidative stress, activation of renin-angiotensin system, and dysregulated sodium transporters and circadian clock. Post-weaning HF diet sex-specifically exacerbates the development of obesity, kidney injury, but not hypertension programmed by maternal HF intake. Better understanding of the sex-dependent mechanisms that underlie HF-induced renal programming will help develop a novel personalized dietary intervention to prevent obesity and related disorders.

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