Men, Hormones, and Kidneys: The Hormonal Secret to Kidney Health Revealed by USC Scientists

Why do male kidneys show greater susceptibility to disease compared to their female counterparts? A mouse study spearheaded by USC Stem Cell researchers suggests testosterone is the key factor.

It’s no secret that female kidneys demonstrate greater resilience against diseases and injuries than their male counterparts. However, there may be a silver lining for men.

New research led by USC Stem Cells and published in the journal Developmental Cell has shed light on how hormonal differences contribute to this disparity and suggests that reducing testosterone could actually enhance the durability of male kidneys.

Professor Andy McMahon, who served as the study’s lead investigator and oversees the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine at USC, emphasized “By exploring how differences emerge in male and female kidneys during development, we can better understand how to address sex-related health disparities for patients with kidney diseases.”

In collaboration with first authors Lingyun “Ivy” Xiong and Jing Liu from McMahon’s Lab, the study discovered that over 1,000 genes are differentially activated in male and female mouse kidneys. Funded by the National Institutes of Health, the team found that these differences are most pronounced in the kidney’s proximal tubule, which is essential for reabsorbing vital nutrients like amino acids and glucose into the bloodstream. Interestingly, these disparities became more evident as the mice hit puberty and continued to intensify into adulthood.

The researchers were particularly interested in how male kidneys could be made more resilient, similar to their female equivalents. They identified testosterone as the primary factor behind this divergence.

To test their hypothesis, they either neutered the male mice before puberty to decrease testosterone levels or neutralized androgen receptors, which are responsible for sensing male sex hormones. Both approaches proved to be effective in ‘feminizing’ the male kidneys.

Interestingly, a three-month calorie restriction—known to indirectly reduce testosterone—yielded similar results. Past research has shown that calorie restriction can help alleviate certain types of kidney injuries in mice.

To restore the ‘masculinity’ of the kidneys in neutered male mice, a simple injection of testosterone sufficed. Conversely, female mice that had their ovaries removed could have their kidneys ‘masculinized’ through testosterone injections.

To validate the relevance of these findings to humans, the researchers evaluated a select set of kidneys from male and female donors. They found a moderate correlation between human and mouse genes, confirming the need for further investigations.

“There is much more work to be done in studying sex-related differences in normal human kidneys,” McMahon concluded. “Given the divergent outcomes for male and female patients with kidney disease and injury, this line of inquiry is important for making progress toward eventually closing the gap on these sex-related health disparities.”

Source: 10.1016/j.devcel.2023.08.010

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