The Role of Hormones in the Differences Between Male and Female Kidneys: How Testosterone Impacts Kidney Health

It is a strange fact: the female kidney is better than the male kidney. Women are therefore less likely to develop kidney disease, the kidneys are damaged less quickly and recover better. How is that possible? The answer is: hormones.

California researchers have found out that sex hormones play a decisive role in the differences between the kidneys of male and female lab mice. In fact, lowering a male’s testosterone level can make his kidneys more “feminine.” This improves the resilience of the male organs. The scientists describe three ways in which they successfully carried out this process.

“We focused on the differences in kidney development between male and female mice to better understand the differences between male and female kidney patients,” said lead researcher Andy McMahon of the Keck School of Medicine out.

Differences in gene activity
The researchers identified a total of more than a thousand genes that are different in male and female mouse kidneys. These differences are particularly evident in the proximal tubule, a part of the kidney where the blood is filtered and a large number of nutrients such as glucose and amino acids flow back into the bloodstream. Almost all differences in gene activity start at the onset of puberty and continue to increase into adulthood.

Two genes (in red and green) that are more active in the kidneys of female mice. Image: Jing Liu/McMahon Lab

Because female kidneys, on average, fare much better against disease and damage, the scientists are curious about how kidney gene activity ‘feminizes’ or ‘masculines’. Research in lab mice showed that the sex hormone testosterone is the main culprit. Can male kidneys be improved by feminizing them?

Successful strategies
The researchers came up with all sorts of tactics and in the end two strategies proved to work equally well: castrating the males before puberty, so that their natural testosterone levels remained low, and removing the androgen receptors, which respond to the male sex hormones. In addition, a fascinating third way has been found to achieve a similar effect and that is to follow a low-calorie diet for three months. Previous research has shown that a low calorie intake can help certain types of kidney damage in mice. Now, this indirect way of lowering testosterone levels has once again been linked to improving kidney health.

Testosterone is key
This process also works the other way. To ‘masculine’ the kidneys of castrated male mice again, the researchers only had to give them a dose of testosterone. And similarly, after a testosterone injection, the kidneys of females whose ovaries were removed before puberty became masculinized.

The scientists performed similar experiments with mouse livers. Although gender-related differences can also be found in this organ, the hormones and underlying factors that determine these differences appear to work completely differently than in the kidneys. According to the team, we can conclude that these organ differences arose independently during the evolutionary process.

Still a lot of work to do
The researchers performed biopsies on human donors and lab mice, after which they were able to map out the genetic similarities and differences. There appears to be quite a large overlap between mice and humans in terms of sex-related differences in the kidneys. “We have a lot more study and work to do before we fully understand the differences between male and female kidneys in humans,” said McMahon.

“There are significant differences between the sexes when looking at kidney disease, kidney damage and the medical recovery process. That is why it is so important to make progress in this area. Step by step we are moving towards a situation in which men no longer suffer from kidney problems more often than women.” But how exactly this should be done, further research will show.

2023-09-05 16:02:42
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