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Cited by 66Ion Transport and Channel RegulationRenin-Angiotensin System StudiesBlood Pressure and Hypertension Studies

Sex differences in solute and water handling in the human kidney: Modeling and functional implications

Open access
Hu, Rui, McDonough, Alicia A., Layton, Anita T.·2021·iScience
DOI 10.1016/j.isci.2021.102667PMC PMC8209279

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Abstract

Abstract Besides the excretion of metabolic wastes, the kidneys regulate homeostasis of electrolytes, pH, metabolites, volume and blood pressure. Sex differences in kidney function and blood pressure have been widely described across many species. Immunoblot analysis has revealed that the kidney of a female rat is not simply a smaller version of a male kidney. Rather, male and female rat kidneys exhibit dimorphic patterns of transporter expression and salt handling, the functional implications of which have been analyzed in a series of previously published modeling studies of rat kidney function. In the present study, we extend the analysis to the human kidney: we developed sex-specific models of solute and water transport in the human kidney, and identified epithelial transport parameters, consistent with patterns found in male and female rats, that yield urine output and excretion rates consistent with known human values. The model predicts that the lower sodium hydrogen exchanger 3 (NHE3) activity in women reduces the fractional reabsorption of Na + , K + , Cl - , and water along the proximal tubule, compared to men, and that the larger load on the distal nephron can be handled by enhanced activities in key Na + transporter such as epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC) in women. Model simulations further indicate that the larger distal transport capacity and proximal transport reserve may better prepare women for elevated demands of pregnancy and lactation. The larger distal transport capacity may also contribute to reduced efficacy of angiotensin converting enzyme inhibitors to lower blood pressure in women. Author summary The kidneys maintain homeostasis by controlling the amount of water, ions, and other substances in the blood. That function is accomplished by the nephrons, which transform glomerular filtrate into urine by an exquisite transport process mediated by a number of membrane transporters. Recently, the distribution of renal transporters along the nephron has been shown to be markedly different between male and female rodents. We postulate that similar sexual dimorphism exists between men and women, and we seek to reveal its physiological implications. We hypothesize that the larger abundance of a renal Na + transport in the proximal tubules in females may also better prepare them for the fluid retention adaptations required during pregnancy and lactation, durint which renal and systemic hemodynamics are both drastically altered by the marked volume expansion and vasodilation. Also, kidneys play a key role in blood pressure regulation, and a popular class of anti-hypertensive medications, angiotensin converting enzymes (ACE) inhibitors, have been reported to be less effective in women. Model simulations suggest that the blunted natriuretic and diuretic effects of ACE inhibition in women can be attributed, in part, to their higher distal baseline transport capacity.

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  • There are known sex differences in renal K+ handling, aldosterone concentration, and plasma K+ concentration.

    “We refer to this as a model of a man, instead of more generally as a human model, due to the known sex differences in renal K+ handling [24–26], ALD concentration [27], and plasma K+ concentration [28], all of which affect K+ homeostasis.”

    From A mathematical model of potassium homeostasis: Effect of feedforward and feedback controls (2022) · cites this paper as [25]

    The Results (page unavailable) predict sex differences in renal K+ reabsorption, supporting the part of the sentence to which this source is cited. But the paper models human transporter differences by assuming that patterns observed in rats translate to humans; it does not establish the renal K+ difference as a known human finding. The sentence cites other sources for aldosterone and plasma K+ concentrations, so those claims are not attributed to this paper. (LLM, conf=0.82)

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  • The major Na+-reabsorbing pathway in the proximal tubule, mediated by NHE3 and NaPi2a, is less active in females, resulting in higher salt delivery to downstream segments.

    “Studies in rodents showed that the major Na + -reabsorbing pathway in the PT, mediated by the Na + /H + exchanger (NHE3) and the Na + -dependent Pi transporter 2a (NaPi2a), is less active in females, resulting in higher salt delivery to downstream segments [ 11 , 12 , 15 , 111 , 112 ].”

    From Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications (2026) · cites this paper as [111]

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Authors
Hu, R., McDonough, A. A., & Layton, A. T.
Affiliations
  • University of Waterloo (CA)
  • University of Southern California (US)
Corresponding author
Layton, Anita T.
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2021-06
Volume
24
Issue
6
Pages
102667
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2021.102667
PMC
PMC8209279
OpenAlex
W3168692467
Cited by
65
References
71
Citations by year
2026: 7 · 2025: 14 · 2024: 7 · 2023: 16 · 2022: 15 · 2021: 6
FWCI
3.45
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UWSpace (University of Waterloo) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (2R01DK083785, R56DK123780)
  • Natural Sciences and Engineering Research Council of Canada
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
Keywords
sex differences, renal function, nephron, sodium transport, proximal tubule, distal nephron, ACE inhibitors, sodium excretion, diuresis, pregnancy and lactation, fluid retention, blood pressure regulation, renal transporters, mathematical modeling

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