Stimulation of constitutive nitric oxide uniquely and compensatorily regulates intestinal epithelial cell brush border membrane Na absorption
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In the mammalian small intestine, sodium is primarily absorbed by Na+/H+ exchange (NHE3) and Na-glucose cotransport (SGLT1) in the brush border membrane (BBM) of villus cells. However, how enhanced cellular constitutive nitric oxide (cNO) may affect NHE3 and SGLT1 remains unclear. Both in vivo in rabbit intestinal villus cells and in vitro IEC-18 cells, administration of NO donor, GSNAP, modestly increased cNO. GSNAP stimulated SGLT1 in villus and IEC-18 cells. The mechanism of stimulation was secondary to an increase in the affinity of SGLT1 for glucose. The change in SGLT1 was not secondary to altered Na-extruding capacity of the cell since Na+/K+-ATPase was decreased by GSNAP treatment. In contrast, GSNAP inhibited NHE3 activity in villus cell BBM. The mechanism of NHE3 inhibition was secondary to reduced BBM transporter numbers. These studies demonstrated that the physiological increase in cNO uniquely regulates mammalian small intestinal NHE3 and SGLT1 to maintain Na homeostasis.
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Enhanced intracellular cNO inhibits NHE3 but stimulates SGLT1 in differentiated human jejunal organoid-derived monolayers.
“Consistent with our previous studies performed in mammalian intestinal epithelial cell models [25], we recently showed that enhanced intracellular cNO inhibits NHE3 but stimulates SGLT1 in differentiated human jejunal organoid-derived monolayers [18].”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [25]
The Discussion reports that increased intracellular cNO inhibits NHE3 and stimulates SGLT1. But it identifies the studied cells as coming from rabbits and rats, in vivo and in vitro, respectively—not differentiated human jejunal organoid-derived monolayers. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe reciprocal regulation between NHE3 and SGLT1 in human enterocytes is consistent with compensatory regulation observed in mammalian intestinal cell models.
“This is consistent with the compensatory regulation between NHE3 and SGLT1 observed in mammalian intestinal cell models [24,25,27], and therefore serves as proof of concept for using siRNA technology in patient-derived organoid monolayers.”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [25]
The differential regulation of NHE3 and SGLT1 by cNO implies functional compensation between the two primary Na absorptive pathways.
“Furthermore, intracellular cNO was shown to differentially regulate NHE3 and SGLT1 in vitro in IEC-18 cells [23,24,25] and in vivo in rabbit small intestine [25,55,56], which implies functional compensation between the two primary Na absorptive pathways.”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [25]
Intracellular cNO differentially regulates NHE3 and SGLT1 in vitro in IEC-18 cells and in vivo in rabbit small intestine.
“Furthermore, intracellular cNO was shown to differentially regulate NHE3 and SGLT1 in vitro in IEC-18 cells [23,24,25] and in vivo in rabbit small intestine [25,55,56], which implies functional compensation between the two primary Na absorptive pathways.”
From Regulation of Enterocyte Brush Border Membrane Primary Na-Absorptive Transporters in Human Intestinal Organoid-Derived Monolayers (2024) · cites this paper as [25]
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Haynes, J., Palaniappan, B., Tsopmegha, E., & Sundaram, U. (2022) · Translational Research · doi:10.1016/j.trsl.2022.04.008 · Cited by 11 · see citing works
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“Consistent with our previous studies performed in mammalian intestinal epithelial cell models [25], we recently showed that enhanced intracellular cNO inhibits NHE3 but stimulates SGLT1 in differentiated human jejunal organoid-derived monolayers [18].”
BackgroundResultInfluentialSelf-citation
- Authors
- Palaniappan, B., Manoharan, P., Arthur, S., Singh, S., Murughiyan, U., & Sundaram, U.
- Affiliations
- Marshall University (US)
- Corresponding author
- Sundaram, Uma
- ORCID
- Venue
- Physiological Reports
- Publisher
- Wiley
- Published
- 2019-05
- Volume
- 7
- Issue
- 9
- Pages
- e14086
- ISSN
- 2051-817X (ISSN-L)
- PMC
- PMC6509550
- OpenAlex
- W2944644955
- Cited by
- 3
- References
- 46
- Citations by year
- 2024: 1 · 2022: 1 · 2019: 1
- FWCI
- 0.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Physiological Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (DK‐67420, DK‐108054, P20GM121299‐01A1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Digestive system and related health
- Keywords
- intestinal sodium absorption, brush border membrane, NHE3, SGLT1, Na+/H+ exchange, Na+/glucose cotransport, Na+/K+-ATPase, Na+ homeostasis, IEC-18 cells
- MeSH terms
- Sodium-Hydrogen Exchanger 3, Sodium-Potassium-Exchanging ATPase, Animals, Cells, Cultured, Intestinal Absorption, Intestinal Mucosa, Intestine, Small, Microvilli, Nitric Oxide, Nitroso Compounds, Penicillamine, Rabbits, Sodium, Sodium-Hydrogen Exchangers, Sodium-Glucose Transporter 1, Rats
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