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Cited by 316Ion Transport and Channel RegulationRenin-Angiotensin System StudiesBlood Pressure and Hypertension Studies

Sexual dimorphic pattern of renal transporters and electrolyte homeostasis

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Veiras, Luciana C., Girardi, Adriana C.C., Curry, Joshua, Pei, Lei, Ralph, Donna L., Tran, An, Castelo-Branco, Regiane C., Pastor-Soler, Nuria +3 more·2017·Journal of the American Society of Nephrology
DOI 10.1681/asn.2017030295PMC PMC5698077
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Abstract

Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did. Compared with the proximal tubule of males, the proximal tubule of females had greater phosphorylation of Na + /H + exchanger isoform 3 (NHE3), distribution of NHE3 at the base of the microvilli, and less abundant expression of Na + /Pi cotransporter 2, claudin-2, and aquaporin 1. These changes associated with less bicarbonate reabsorption and higher lithium clearance in females. The distal nephrons of females had a higher abundance of total and phosphorylated Na + /Cl − cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na + channel (ENaC) α and γ subunits, which associated with a lower baseline plasma K + concentration. A K + -rich meal increased the urinary K + concentration and decreased the level of renal phosphorylated NCC in females. Notably, we observed similar abundance profiles in female versus male C57BL/6 mice. These results define sexual dimorphic phenotypes along the nephron and suggest that lower proximal reabsorption in female rats expedites excretion of a saline load and enhances NCC and ENaC abundance and activation, which may facilitate K + secretion and set plasma K + at a lower level.

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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 [26]

  • Data from mice and rats confirm a sex difference in basal plasma K+, and show that females are more susceptible to hypokalemia while males are more susceptible to hyperkalemia.

    “Consistent with findings in humans, data from mice [ 12 , 46 , 47 ] and rats [ 48 , 49 ] confirm a sex difference in basal plasma K + , and show that females are more susceptible to hypokalemia [ 46 , 47 , 49 ] while males are more susceptible to hyperkalemia [ 49 – 53 ].”

    From Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications (2026) · cites this paper as [12]

  • 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 [12]

  • ENaC expression is higher in females, likely driven by the combined effects of the sex chromosome complement and E2-mediated activation of the estrogen receptor α (ERα).

    “On the other hand, observations in mice and rats showed that ENaC expression is higher in females, likely driven by the combined effects of the sex chromosome complement and E2-mediated activation of the estrogen receptor α (ERα) [ 12 , 15 , 110 , 115 , 116 ] (Fig. 1 ).”

    From Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications (2026) · cites this paper as [12]

  • Na+ reabsorption mediated by NKCC2 in the thick ascending limb and NCC in the distal convoluted tubule is higher in females, more likely driven by E2.

    “Contrasting with the lower Na + reabsorption in the female PT, Na + reabsorption mediated by the furosemide-sensitive Na + /K + /Cl − cotransporter (NKCC2) in the TAL and thiazide-sensitive NCC in the DCT is higher in females [ 10 – 17 ], more likely driven by E2 [ 16 , 113 , 114 ].”

    From Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications (2026) · cites this paper as [12]

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Authors
Veiras, L. C., Girardi, A. C. C., Curry, J., Pei, L., Ralph, D. L., Tran, A., Castelo-Branco, R. C., Pastor-Soler, N., Arranz, C. T., Yu, A. S. L., & McDonough, A. A.
Affiliations
  • Department of Integrative Anatomical Sciences and
  • Universidade de São Paulo (BR)
  • University of Kansas Medical Center (US)
  • Department of Physiology and Biophysics, Biomedical Sciences Institute, University of São Paulo, São Paulo, Brazil; and
  • Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California;
  • Universidad de Buenos Aires (AR)
Corresponding author
  • Veiras, Luciana C.
  • Ralph, Donna L.
  • Tran, An
  • McDonough, Alicia A.
ORCID
Venue
Journal of the American Society of Nephrology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-08-03
Volume
28
Issue
12
Pages
3504-3517
ISSN
  • 1046-6673 (ISSN-L)
  • 1533-3450
DOI
10.1681/asn.2017030295
PMC
PMC5698077
OpenAlex
W2742226233
Cited by
316
References
89
Citations by year
2026: 29 · 2025: 40 · 2024: 48 · 2023: 42 · 2022: 42 · 2021: 35 · 2020: 35 · 2019: 21 · 2018: 21 · 2017: 2 · 2016: 1
FWCI
8.83
Type
journal article
Language
en
Open access
Locations
  • Journal of the American Society of Nephrology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01dk083785-11)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-083785, F30DK109605, R01DK062283)
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
sexual dimorphism, renal transporters, electrolyte balance, sodium chloride cotransporter, epithelial sodium channel, NHE3, claudin-2, claudin-7, aquaporin-1, bicarbonate reabsorption, potassium secretion, pressure natriuresis, plasma potassium, mice
MeSH terms
Animals, Biological Transport, Blood Pressure, Electrolytes, Female, Homeostasis, Kidney, Kidney Tubules, Male, Mice, Inbred C57BL, Microvilli, Nephrons, Phosphorylation, Potassium, Sex Characteristics, Sodium, Rats, Sprague-Dawley, Membrane Transport Proteins, Mice, Rats

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