Sleep restriction during pregnancy can induce hypertension in offspring

Experiments with rats show that sleeping less than necessary during pregnancy may impair renal development in offspring and predispose them to disease.

By Karina Toledo, in Foz do Iguaçu (Paraná)  |  Agência FAPESP – Sleeping too little during pregnancy can lead to hypertension and cardiovascular disease in adult offspring, according to an experiment conducted with rats at the Federal University of São Paulo (UNIFESP) in Brazil.

The findings were presented by Guiomar Nascimento Gomes, a professor in UNIFESP’s Physiology Department, at the 31st Annual Meeting of the Federation of Experimental Biology Societies (FeSBE), held in Foz do Iguaçu, Paraná State. The research project was supported by FAPESP.

“Sleep restriction is known to be associated with various kinds of hormone alteration,” Gomes told Agência FAPESP. “Our findings showed offspring can be affected by the consequences of sleep restriction when it occurs during pregnancy. Of course, observations in rats can’t be directly transposed to humans, but this is initial evidence.”

According to Gomes, biologists consider seven to eight hours of sleep ideal for rats as well as humans. In the experiment, pregnant rats were allowed to sleep only four hours per day in the last week of pregnancy, which Gomes says corresponds to the third trimester of pregnancy in humans, since a rat fetus takes about 21 days to develop in preparation for birth.

“Our main aim was to investigate the effect of maternal sleep deprivation on renal function in offspring – the kidneys are formed precisely in the final phase of gestation,” Gomes said. “Previous research by our group showed sleep restriction in the last week of pregnancy was sufficient to induce significant alterations.”

Compared with the control group, offspring born to sleep-deprived rats exhibited a reduction in the number of nephrons, the structural units of the kidney that filter blood and form urine. These animals also exhibited glomerular hypertrophy and an altered glomerular filtration rate compared with control offspring.

The researchers also observed increased sympathetic activity in the heart, which tends to favor a rise in heart rate. According to Gomes, the animals appeared to have suffered from damage to their baroreflex, an important central nervous system mechanism for rapid adjustment of arterial pressure.

“When blood pressure rises for whatever reason, the baroreflex is normally activated, and this leads to a series of changes in the organism that lower the heart rate and blood pressure. In these rats, this response didn’t occur as it should have,” Gomes said.

Because of these alterations, male offspring of sleep-deprived rats developed hypertension shortly after reaching adult age when they were about three months old (roughly equivalent to 25 years old for humans). Blood pressure in female offspring, however, remained within the range considered normal, although it was higher than in the control group.

“Female hormones protect the cardiovascular system by contributing to the production of nitric oxide, a potent vasodilator that improves renal function,” Gomes explained.

In a second experiment, the ovaries of female offspring of sleep-deprived rats were removed at an early age and these offspring also became hypertensive at about eight months. The results of this study were published in August in Physiological Reports.

The results of the experiment with male offspring had previously been described in PLoS One and Clinics.

Fetal programming

For Gomes, the stress suffered by pregnant females due to sleep restriction and the resulting rise in release of corticosterone, the rodent hormone equivalent to cortisol in humans, could be one of the causes of impaired kidney development in their offspring.

“A placental enzyme known as 11-beta-hydroxysteroid dehydrogenase, or 11β-HSD, protects the fetus from the stress hormone, but by late pregnancy this enzyme almost vanishes because the fetus needs corticoids to complete the maturation process. Too much corticosterone could therefore cause damage,” Gomes said.

More research needs to be done to corroborate this hypothesis. Another possibility, according to Gomes, would be to evaluate, in the offspring’s central nervous system, the expression of proteins that make up the renin-angiotensin-aldosterone system, a well-known regulator of blood pressure.

Gomes said the kidney damage to offspring in this sleep restriction model was somewhat similar to that observed in another study performed at UNIFESP by Frida Zaladek Gil, in which pregnant rats were subjected to diet restriction.

“These are fetal programming models that appear to stimulate the development of high blood pressure,” Gomes said. “When the fetal organism is subjected to an adverse condition, it prioritizes the development of certain organs to the detriment of others. Renal development is impaired in order not to damage the heart and brain, for example.”

In Brazil, at least 25% of the population suffers from hypertension, according to Gomes, and experts believe these cases are undernotified. “The root cause is often unknown. Fetal programming could play a major role. Several factors can contribute to high blood pressure. We need to know about them all. I expect the results of this study will contribute to a better understanding of the importance of getting enough sleep,” she said.

Effects of diabetes

Also during the FeSBE meeting, Gomes presented the results of another study by her group showing how uncontrolled diabetes during pregnancy can affect renal activity and increase the risk of hypertension in offspring. This experiment was also performed in rats.

“The renal damage observed in this model was somewhat different. The number of nephrons was not reduced and yet the offspring of diabetic rats exhibited significant renal dysfunction, with a lower glomerular filtration rate and reduced urine flow. They also developed hypertension in adult life,” Gomes said.

The dysfunction observed in this model, she added, is caused by increased renal sympathetic activity, which stimulates the secretion of the enzyme renin, and this in turn promotes the production of angiotensin and aldosterone, raising blood pressure and inducing vasoconstriction.

In this experiment, the UNIFESP group succeeded in reversing renal dysfunction and controlling blood pressure by means of a surgical procedure that disconnected some of the nerves around the renal artery in a technique known as renal sympathetic denervation. The results were published in 2013 in the American Journal of Physiology – Renal Physiology.