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Sex differences in renal transporters: assessment and functional consequences

Nature Reviews Nephrology volume 20, pages 21–36 (2024)Cite this article

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Abstract

Mammalian kidneys are specialized to maintain fluid and electrolyte homeostasis. The epithelial transport processes along the renal tubule that match output to input have long been the subject of experimental and theoretical study. However, emerging data have identified a new dimension of investigation: sex. Like most tissues, the structure and function of the kidney is regulated by sex hormones and chromosomes. Available data demonstrate sex differences in the abundance of kidney solute and electrolyte transporters, establishing that renal tubular organization and operation are distinctly different in females and males. Newer studies have provided insights into the physiological consequences of these sex differences. Computational simulations predict that sex differences in transporter abundance are likely driven to optimize reproduction, enabling adaptive responses to the nutritional requirements of serial pregnancies and lactation — normal life-cycle changes that challenge the ability of renal transporters to maintain fluid and electrolyte homeostasis. Later in life, females may also undergo menopause, which is associated with changes in disease risk. Although numerous knowledge gaps remain, ongoing studies will provide further insights into the sex-specific mechanisms of sodium, potassium, acid–base and volume physiology throughout the life cycle, which may lead to therapeutic opportunities.

Key points

  • Renal tubule organization differs in female compared with male rodents, notably in the abundance and expression of transporters in individual segments; generally, androgens regulate transporter abundance along the proximal tubule and oestrogens regulate transporter abundance along the distal tubule.

  • Compared with males, female rats exhibit lower fractional reabsorption of sodium along the proximal nephron (associated with a lower activity of NHE3 and lower abundance of claudin2 and AQP1) and higher fractional reabsorption of sodium along distal segments (associated with a higher abundance of NKCC2, NCC, ENaC and phosphorylated AQP2).

  • Female rats excrete a saline load more rapidly than males and achieve sodium homeostasis with a high salt diet more rapidly than males; moreover, female, but not male, diabetic mice maintain normotension when administered a high-salt diet.

  • Angiotensin infusion provokes similar changes in blood pressure, ENaC activation and K+ loss in both sexes, along with a rise in the expression of distal renal tubule transporters and a lowering of proximal transporters in females.

  • Male and female kidneys differ in the mechanisms used to maintain acid–base homeostasis; for example, they demonstrate differences in baseline ammoniagenesis and their acid–base transporters, and prioritize different adaptations to acid load; key differences are androgen receptor dependent.

  • Computer simulations of pregnant rat kidney function indicate that known sex differences in renal transporters can serve to prepare females to meet the fluid and electrolyte demands of the offspring.

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Fig. 1: Female-specific changes in kidney function that occur through life stages.
Fig. 2: Sex- and species-specific differences in the abundance of renal transporters along the renal tubule.
Fig. 3: Regulation of selected sodium transporters in female versus male mice.
Fig. 4: Expression of sex hormone genes along the renal tubule.
Fig. 5: Impact of transporter sex differences on fluid and electrolyte handling along the renal tubule.

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Acknowledgements

A.A.M. discloses support for the research of this work from the National Institutes of Health (DK083875). A.N.H. discloses support for the research of this work from the National Institutes of Health (K08DK120873). L.(I.)X. discloses support for the research of this work from the National Institutes of Health (R01 DK126925-01). A.T.L. discloses support for the research of this work from: the Canada 150 Research Chairs program, the Natural Sciences and Engineering Research Council (NSERC Discovery award: RGPIN-2019-03916) and the Canadian Institutes of Health Research of Canada, and the Canadian Institutes of Health Research (CIHR) [TNC-174963].

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  1. Lingyun (Ivy) Xiong

    Present address: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA

Authors and Affiliations

  1. Department of Physiology and Neuroscience, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Alicia A. McDonough

  2. Department of Small Animal Clinical Sciences, University of Florida, College of Veterinary Medicine, Gainesville, FL, USA

    Autumn N. Harris

  3. Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Lingyun (Ivy) Xiong

  4. Departments of Applied Mathematics and Biology, University of Waterloo, Waterloo, Ontario, Canada

    Anita T. Layton

  5. Cheriton School of Computer Science, University of Waterloo, Waterloo, Ontario, Canada

    Anita T. Layton

  6. School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada

    Anita T. Layton

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McDonough, A.A., Harris, A.N., Xiong, L.(. et al. Sex differences in renal transporters: assessment and functional consequences. Nat Rev Nephrol 20, 21–36 (2024). https://doi.org/10.1038/s41581-023-00757-2

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