A recent study, conducted by the USC Stem Cell and published in Developmental Cell, has explored the genetic factors that contribute to the gender-based differences in kidney health between male and female mice. Two genes, Gsta4 and Cyp4a14, were identified as being particularly active in female mouse kidneys, which are generally more resilient to diseases and injuries compared to male kidneys. The study was led by Professor Andy McMahon, who also serves as the director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine of USC.
Co-authors Lingyun “Ivy” Xiong and Jing Liu from the McMahon Lab collaborated on this research, which was funded by the National Institutes of Health. They found over 1,000 genes that displayed varying levels of activity between male and female kidneys. These differences were most noticeable in the proximal tubule section of the kidney, an area responsible for the reabsorption of essential nutrients back into the bloodstream. Interestingly, these gender-based variations in gene activity became evident as the mice approached puberty and intensified upon reaching sexual maturity.
The researchers examined why female kidneys typically have greater resilience to disease and injury. Their investigation revealed that testosterone plays a significant role in determining whether the kidneys become “masculinized” or “feminized.” To induce a more feminine kidney structure in male mice, they employed two methods: either castrating the males before puberty, which decreased their testosterone levels, or eliminating androgen receptors that are responsive to male sex hormones.
Remarkably, a three-month period of calorie restriction also led to similar “feminization” of the kidneys by indirectly lowering testosterone levels. Previous studies have shown that calorie restriction can alleviate certain types of kidney injuries in mice.
To reverse the feminization in castrated males, testosterone injections were sufficient. Likewise, injecting testosterone into female mice whose ovaries had been removed before puberty resulted in “masculinization” of their kidneys.
The study also delved into liver differences between male and female mice, revealing distinct hormone-driven factors that account for these gender differences. This suggests that these variations evolved independently in each organ.
The researchers also attempted to identify if the same genes affect gender-specific kidney health in humans by analyzing a limited sample of male and female donor kidneys and biopsies. While there was some overlap between human and mouse genes, more research is needed to fully understand the implications of these findings for human kidney health.
Professor McMahon emphasized the importance of continuing to study these gender-based health disparities, particularly in the context of divergent outcomes for male and female patients suffering from kidney ailments.
The entire research project received federal funding from the National Institutes of Health under grants R01DK126925 and R35GM143019, as well as from the National Science Foundation under grant DMS2045327. Additional contributors to this study include Kari Koppitch, Jin-Jin Guo, and Adam L. MacLean from USC; Zhen Miao and Junhyong Kim from the University of Pennsylvania; and Fan Gao, Ingileif B. Hallgrimsdottir, and Lior Pachter from the California Institute of Technology.
Reference: “Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney” by Lingyun Xiong, Jing Liu, et al., published on 5 September 2023 in Developmental Cell. DOI: 10.1016/j.devcel.2023.08.010.
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Frequently Asked Questions (FAQs) about Kidney Resilience
What was the focus of the USC Stem Cell study on kidney health?
The USC Stem Cell study investigated the influence of gender hormones on kidney resilience, particularly the role of testosterone in “feminizing” male kidneys to enhance their ability to withstand diseases and injuries.
What are the key findings of the research?
The research identified over 1,000 genes with varying activity levels in male and female mouse kidneys, with significant differences in the proximal tubule section. Testosterone emerged as a major factor in determining kidney “masculinization” or “feminization.” Castration, androgen receptor removal, and calorie restriction were all effective in “feminizing” male kidneys.
How did the study relate to human kidney health?
While the study analyzed some human kidney samples, there was only modest overlap between human and mouse genes in terms of gender-related differences. Further research is needed to fully understand the implications for human kidney health.
What potential applications could arise from this research?
Understanding the role of gender hormones in kidney health could pave the way for addressing gender-based health disparities in kidney diseases. It may lead to novel approaches to enhance kidney resilience and improve patient outcomes.
Who were the main contributors to this research, and what funding supported it?
The study was led by Professor Andy McMahon from USC Stem Cell and received federal funding from the National Institutes of Health and the National Science Foundation. Additional contributors included researchers from USC, the University of Pennsylvania, and the California Institute of Technology.
More about Kidney Resilience
- USC Stem Cell
- Developmental Cell Study
- National Institutes of Health
- National Science Foundation
- University of Pennsylvania
- California Institute of Technology
