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Sexual Dimorphic Pattern of Renal Transporters and Electrolyte Homeostasis
Open accessAbstract
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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“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“Related to K + handling, the study confirmed that Na + /K + /Cl − cotransporter (NKCC2), NCC, and ENaC exhibit higher basal expression in females [ 15 ], confirming previous literature [ 10 – 17 ].”
From Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications (2026) · cites this paper as [12]
In the citing paper
“Studies examining sex differences in basal aldosterone levels in rodents have yielded conflicting results reporting higher levels in males [ 129 ], in females [ 121 , 130 ], or no difference between sexes [ 12 , 131 ]”
From Sex differences in potassium regulation: evidence, molecular mechanisms and clinical implications (2026) · cites this paper as [12]
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Clase, C. M., Carrero, J.-J., Ellison, D. H., Grams, M. E., Hemmelgarn, B. R., Jardine, M. J., Kovesdy, C. P., Kline, G. A., Lindner, G., Obrador, G. T., et al. (2020) · Kidney International · doi:10.1016/j.kint.2019.09.018 · Cited by 498
Sex-specific differences in hypertension and associated cardiovascular disease
Colafella, K. M. M., & Denton, K. M. (2018) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.189 · Cited by 505
Animal Models of Hypertension: A Scientific Statement From the American Heart Association
Lerman, L. O., Kurtz, T. W., Touyz, R. M., Ellison, D. H., Chade, A., Crowley, S. D., Mattson, D. L., Mullins, J. J., Osborn, J. L., Eirin, A., et al. (2019) · Hypertension · doi:10.1161/hyp.0000000000000090 · Cited by 351
Onishi, A., Fu, Y., Patel, R., Darshi, M., Crespo-Masip, M., Huang, W., Song, P., Freeman, B., Kim, Y. C., Soleimani, M., et al. (2020) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00264.2020 · Cited by 206
A Comprehensive Map of mRNAs and Their Isoforms across All 14 Renal Tubule Segments of Mouse
Chen, L., Chou, C.-L., & Knepper, M. A. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020101406 · Cited by 208
Metadata
- 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
- Published
- 2017-08-03
- Volume
- 28
- Issue
- 12
- Pages
- 3504-3517
- ISSN
- 1046-6673 (ISSN-L)
- 1533-3450
- 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
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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