Na-glucose and Na-neutral amino acid cotransport are uniquely regulated by constitutive nitric oxide in rabbit small intestinal villus cells

Coon, Steven; Kim, Jim; Shao, Guohong; Sundaram, Uma

doi:10.1152/ajpgi.00124.2005

Cited by 19 publications

(25 citation statements)

References 21 publications

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“…Similar to what was observed in vitro in IEC-18 cells, in vivo inhibition of cNO inhibited SGLT1 in rabbit intestinal villus cell BBM while stimulating NHE3 in the same cells. Furthermore, the mechanism of alteration of SGLT1 and NHE3 when cNO is directly inhibited in vitro in IEC-18 cells is similar to that seen during in vivo inhibition of cNO in rabbits (3,25). Taken together these results suggest that the effects of cNO on Na absorption in the intestine are potentially broadly applicable.…”

Section: Discussionsupporting

confidence: 55%

“…Therefore, whether there is in fact a compensatory linkage between these two BBM transport pathways has not been considered before this study. In vivo inhibition of cNO production in rabbits has been demonstrated to inhibit SGLT1 in villus cells (3). In another study stimulation of villus cell NHE3 was demonstrated on in vivo inhibition of cNO in rabbits (4).…”

Section: Discussionmentioning

confidence: 98%

“…Na-K-ATPase was measured from cell homogenates as previously described (3,8). Specific activity was expressed as nanomoles Pi released per milligram protein per minute.…”

Section: Methodsmentioning

confidence: 99%

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Constitutive nitric oxide differentially regulates Na-H and Na-glucose cotransport in intestinal epithelial cells

Coon¹,

Kekuda²,

Saha³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Coon S, Kekuda R, Saha P, Talukder JR, Sundaram U. Constitutive nitric oxide differentially regulates Na-H and Na-glucose cotransport in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 294: G1369-G1375, 2008. First published March 6, 2008 doi:10.1152/ajpgi.00063.2008.-Previous in vivo studies suggest that constitutive nitric oxide (cNO) can regulate Na-glucose cotransport (SGLT1) and Na-H exchange (NHE3) in rabbit intestinal villus cells. Whether these two primary Na absorbing pathways are directly regulated by cNO and the mechanisms of this regulation in the enterocyte is not known. Thus nontransformed rat small intestinal epithelial cells (IEC-18) were treated with N G -nitro-L-arginine methyl ester (L-NAME), which directly decreased cNO in these cells. L-NAME treatment decreased SGLT1 in IEC-18 cells. Kinetic studies demonstrated that the mechanism of inhibition was secondary to a decrease in the affinity of the cotransporter for glucose without a change in the number of cotransporters. In contrast, L-NAME treatment increased NHE3 in IEC-18 cells. Kinetic studies demonstrated that the mechanism of stimulation was by increasing the number of the exchangers without a change in the affinity for Na. Quantitative RT-PCR (RTQ-PCR) and Western blot analysis of SGLT1 demonstrated no change in mRNA and protein, respectively. RTQ-PCR and Western blot analysis of NHE3 indicated that NHE3 was increased by L-NAME treatment by an increase in mRNA and protein, respectively. These results indicate that decreased cNO levels directly mediate the inhibition of SGLT1 and stimulation of NHE3 in intestinal epithelial cells. Thus cNO directly but uniquely regulates the two primary Na-absorptive pathways in the mammalian small intestine. glucose absorption; regulation of transport; NHE3; SGLT1; Na absorption IN THE MAMMALIAN SMALL INTESTINE there are two major Naabsorptive pathways, coupled NaCl absorption and Na-glucose cotransport (28,29). Coupled NaCl absorption occurs via the duel operation of Na-H exchange (NHE3) and Cl-HCO 3 exchange. Na-glucose cotransport (SGLT1) is a secondary active transport process requiring a favorable intracellular Na gradient provided by Na-K-ATPase on the basolateral membrane (BLM) of villus cells (7). Both NHE3 and SGLT1 have been demonstrated to be present in the brush border membrane (BBM)-absorptive villus cells, but not in the secretory crypt cells in the rabbit small intestine (4,7,11,26).Nitric oxide (NO) is an important and highly active molecule that regulates many functions in the gastrointestinal tract. Small amounts of constitutive NO (cNO) is produced by intestinal epithelial cells as well as the nervous system, musculature, and endothelium to regulate normal physiological functions. cNO has been shown to regulate mucosal blood flow, mucus secretion, and intestinal motility (12,19,23,27). In contrast, large quantities of NO produced by inducible nitric oxide (iNO) synthase is thought not to be beneficial. For example, it is thought to contribute to as well as prolon...

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 98%

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Constitutive nitric oxide differentially regulates Na-H and Na-glucose cotransport in intestinal epithelial cells

Coon¹,

Kekuda²,

Saha³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

Self Cite

View full text Add to dashboard Cite

show abstract

“…This was hypothesised to be due to increased translation of SGLT1 and/or by translocation of SGLT1 protein from an intracellular location to the plasma membrane [38]. Additionally, regulation of SGLT1-mediated glucose transport through changes in affinity has also been shown in vitro [49, 50]. These results collectively suggest that chronic insulin-induced hypoglycaemia would cause translocation and/or upregulation of SGLT1 levels.…”

Section: Discussionmentioning

confidence: 99%

Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

Jensen

Mølck

Chapman

et al. 2017

International Journal of Endocrinology

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The brain is vulnerable to hypoglycaemia due to a continuous need of energy substrates to meet its high metabolic demands. Studies have shown that severe acute insulin-induced hypoglycaemia results in oxidative stress in the rat brain, when neuroglycopenia cannot be evaded despite increased levels of cerebral glucose transporters. Compensatory measures in the brain during chronic insulin-induced hypoglycaemia are less well understood. The present study investigated how the brain of nondiabetic rats copes with chronic insulin-induced hypoglycaemia for up to eight weeks. Brain level of different substrate transporters and redox homeostasis was evaluated. Hyperinsulinaemia for 8 weeks consistently lowered blood glucose levels by 30–50% (4–6 mM versus 7–9 mM in controls). The animals had increased food consumption, body weights, and hyperleptinaemia. During infusion, protein levels of the brain neuronal glucose transporter were decreased, whereas levels of lipid peroxidation products were unchanged. Discontinued infusion was followed by transient systemic hyperglycaemia and decreased food consumption and body weight. After 4 weeks, plasma levels of lipid peroxidation products were increased, possibly as a consequence of hyperglycaemia-induced oxidative stress. The present data suggests that chronic moderate hyperinsulinaemic hypoglycaemia causes increased body weight and hyperleptinaemia. This is accompanied by decreased neuronal glucose transporter levels, which may be leptin-induced.

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“…Studies using diabetic patients have also shown a link of SGLT1 to glucose transporter 2 (GLUT2) in intestinal villus cells and that SGLT1 function stimulates the expression of GLUT2 in the BBM of intestinal epithelia. Indirect linkage between NHE3 and SGLT1 mediated by intracellular sodium was also postulated as a result of the in vivo studies to inhibit constitutive nitric oxide production in the rabbit small intestine (4,5).…”

Section: ·30 Smentioning

confidence: 99%

Reciprocal regulation of the primary sodium absorptive pathways in rat intestinal epithelial cells

Coon

Kekuda

Saha

et al. 2011

American Journal of Physiology-Cell Physiology

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Coon S, Kekuda R, Saha P, Sundaram U. Reciprocal regulation of the primary sodium absorptive pathways in rat intestinal epithelial cells. Am J Physiol Cell Physiol 300: C496 -C505, 2011. First published December 9, 2010 doi:10.1152/ajpcell.00292.2010.-Sodium absorption in the mammalian small intestine occurs predominantly by two primary pathways that include Na/H exchange (NHE3) and Na-glucose cotransport (SGLT1) on the brush border membrane (BBM) of villus cells. However, whether NHE3 and SGLT1 function together to regulate intestinal sodium absorption is unknown. Nontransformed small intestinal epithelial cells (IEC-18) were transfected with either NHE3 or SGLT1 small interfering RNAs (siRNAs) and were grown in confluent monolayers on transwell plates to measure the effects on Na absorption. Uptake studies were performed as well as molecular studies to determine the effects on NHE3 and SGLT1 activity. When IEC-18 monolayers were transfected with silencing NHE3 RNA, the cells demonstrated decreased NHE3 activity as well as decreased NHE3 mRNA and protein. However, in NHE3 siRNAtransected cells, SGLT1 activity, mRNA, and protein in the BBM were significantly increased. Thus, inhibition of NHE3 expression regulates the expression and function of SGLT1 in the BBM of intestinal epithelial cells. In addition, IEC-18 cells transected with silencing SGLT1 RNA demonstrated an inhibition of Na-dependent glucose uptake and a decrease in SGLT1 activity, mRNA, and protein levels. However, in these cells, Na/H exchange activity was significantly increased. Furthermore, NHE3 mRNA and protein levels were also increased. Therefore, the inhibition of SGLT1 expression stimulates the transcription and function of NHE3 and vice versa in the BBM of intestinal epithelial cells. Thus this study demonstrates that the major sodium absorptive pathways together function to regulate sodium absorption in epithelial cells.

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Na-glucose and Na-neutral amino acid cotransport are uniquely regulated by constitutive nitric oxide in rabbit small intestinal villus cells

Cited by 19 publications

References 21 publications

Constitutive nitric oxide differentially regulates Na-H and Na-glucose cotransport in intestinal epithelial cells

Constitutive nitric oxide differentially regulates Na-H and Na-glucose cotransport in intestinal epithelial cells

Chronic Hyperinsulinaemic Hypoglycaemia in Rats Is Accompanied by Increased Body Weight, Hyperleptinaemia, and Decreased Neuronal Glucose Transporter Levels in the Brain

Reciprocal regulation of the primary sodium absorptive pathways in rat intestinal epithelial cells

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