Estrogen Shields Kidneys from Chronic Disease

Chronic kidney disease is an increasing global health problem that affects approximately 700 million people worldwide.¹ It is a progressive condition wherein the kidneys lose their ability to filter waste and excess fluid from the blood, which consequently affects other organs of the body. In fact, the disease not only increases the chances of kidney failure, but also of developing cardiovascular disease, putting it on the path to be the fifth leading cause of death worldwide by 2040.²

One of the leading risk factors of chronic kidney disease is male sex.³ However, the incidence rates of the disease are also high in postmenopausal females or those who have had their ovaries removed. Considering these trends, Paola Romagnani, a nephrologist at the University of Florence, hypothesized that female sex hormones—such as estrogen—could play a role in shielding the kidneys from deterioration. Now, in a study published in Science, Romagnani and her team showed that estrogen signaling promoted regeneration of key filtering cells called podocytes in female mouse kidneys, thus protecting the organs from disease during reproductive years.⁴ Their findings could pave way for potential therapeutics in the future.

The adult kidney has a limited capacity to regenerate injured or diseased podocytes from renal progenitor cells (RPCs). Romagnani and her team assessed how sex affected the limits of podocyte renewal in mice at different ages. In transgenic mice with fluorescently labeled RPCs, the researchers found that compared to male mice, female mice had more RPCs that could generate more podocytes. Notably, the differences emerged after the mice hit puberty, which indicated a role for sex hormones. The team tested their theory by assessing the effects of estrogen, progesterone, and testosterone on cultured human RPCs and observed that the former two promoted proliferation of the cells and their differentiation into podocytes.

Next, Romagnani and her group analyzed how disrupting estrogen signaling affected podocyte renewal in animals. They generated female mice without estrogen receptors in the RPCs and observed that their rates of podocyte generation were no different from that of male mice, and more than five times lower than in female mice.

One of the times when kidneys rev up their activity is during pregnancy. A pregnant person’s kidneys increase their filtration rates by 40-50 percent. The researchers assessed how podocyte numbers adapt to this increased demand by tracing the fate of mouse RPCs with or without estrogen receptors. They found that estrogen signaling in RPCs promoted the generation of new podocytes during pregnancy. A disruption of this adaptive process led to preeclampsia, a serious complication that involves onset of high blood pressure and damage to maternal organs like kidneys or liver. The pups of preeclamptic mice had lower kidney weights and fewer filtering units, thus reducing their kidney resilience to injury later in life. To determine how human kidneys adapt to the elevated filtration demands, the team analyzed the urine of pregnant women and healthy controls and found shed RPCs only in the former group, which differentiated into podocytes in lab cultures.

These findings highlight the mechanistic link between kidney health, preeclampsia, and estrogen signaling, offering avenues for further research and development of improved treatments.