Sex Differences in Fetal Programming of Blood Pressure and Kidney Gene Expression of Intrauterine Growth Restricted Mouse Model

Abstract

The fetal environment is critical in determining future cardiovascular‐renal function in adulthood. Intrauterine growth restriction (IUGR) results in an unfavorable intrauterine milieu, and can lead to hypertension, renal, and cardiovascular disease of the offspring later in life. However, the underlying mechanisms linking IUGR to cardiovascular and renal afflictions remain unclear. IUGR offspring exhibit impaired kidney development. Furthermore, IUGR reprograms kidney function, resulting in an increase in blood pressure (BP) and susceptibility to kidney injury in the adult. While some renal factors have been postulated, others remain to be elucidated. Here, we have utilized a relevant preclinical mouse model of IUGR induced by reduced uterine perfusion pressure (RUP) to explore the effect of IUGR on renal gene expression patterns as well as sex differences. Pregnant C57bl/6J mice underwent sham or reduced uterine perfusion (RUP) at day 13 of gestation with delivery at full term. IUGR offspring (from RUP dam) had a lower birth weight than control (p<0.05). At 24 weeks of age, control and IUGR mice were subjected to BP measurement. Kidney tissues from control and IUGR mice were isolated and mRNA from these tissues was subjected to microarray analysis to determine differential gene expression. We found that male IUGR offspring had a significantly higher BP compared to male controls (p<0.05). No significant differences in BP were found between female IUGR and female controls, suggesting that sex differences in IUGR programs increased BP in mice. Microarray analysis, at a statistical cutoff of p < 0.05, demonstrates clear sex differences between IUGR and control mice. Of the total number of genetic elements (n = 39,724), 8,356 were significantly different due to IUGR alone, with the majority of these differences occurring in the males (8,319). Network analysis indicated a strong effect on several pathways such as protein processing in the endoplasmic reticulum, oxidative phosphorylation, and mTOR signaling pathways in male IUGR compared to male controls. Interestingly, two pathways (PPAR signaling and AMPK signaling) were significantly altered by IUGR in the female group. In conclusion, there is a clear sex difference in the effect of IUGR on BP and kidney gene expression. The functional implications of these novel factors need to be further investigated.Support or Funding InformationDr. Intapad was supported by funding from the AHA 16SDG27770041, ASN Kidney Research Career Development grant, and grant P20GM109036 K. J. Maeda was supported by National Institutes of Health Grants T32HL‐105324 and 20PRE352000021. Dr. Garrett was supported by P20GM‐103476, P20GM‐104357 and P20GM‐121334