Acute kidney injury: Low testosterone levels may help protect women

Men get acute kidney injury – where kidney performance suddenly declines – at a higher rate than women. An experiment with mice suggests that this could be related to having higher levels of testosterone

By Grace Wade

Low testosterone levels appear to protect kidney cells in mice from cell death. The finding could explain why women are at a lower risk of acute kidney injury than men.

Tomokazu Souma at Duke University in North Carolina collected kidney samples from eight mice – four females and four males – and genetically sequenced them. They identified 128 genes that were expressed differently between the two sexes and further analysis revealed many of these genes were related to a particular cell process called NRF2. This process is known to protect against ferroptosis, a form of cell death that is a driver of acute kidney injury in people, where the kidneys suddenly decline in performance.

To try to work out whether sex hormones affect the protection provided by NRF2, the team, in a separate experiment, removed the ovaries of six female mice and the testicles of four male mice so that the mice would have less oestrogen and less testosterone respectively than normal.

They sequenced the animals’ genes three to four weeks later and found that, in the female mice, the genes involved in NRF2 weren’t affected by the procedure. But for the male mice, there was over a fivefold increase, on average, in the expression of two of the genes – GSTA4 and CBR1 – when compared with mice with testicles.

This suggests that testosterone reduces the NRF2 process in male mice, leaving them more susceptible to ferroptosis in their kidneys and potentially explaining why men have higher incidences of kidney injury, says Souma.

Oestrogen may still play a role in the sex differences for kidney disease, however. Another experiment from the team found that female mice without ovaries had worse kidney function than those that did.

“There are many different mechanisms that have been explored with respect to sex differences in acute kidney injury, and they all seem plausible,” says Joel Neugarten at Montefiore Medical Center in New York. “And it’s probably a combination of different factors that explain the difference.”

Journal reference: Cell Reports, DOI: 10.1016/j.celrep.2022.111610