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

Coon, Steven; Kekuda, Ramesh; Saha, Prosenjit; Sundaram, Uma

doi:10.1152/ajpcell.00292.2010

Cited by 25 publications

(21 citation statements)

References 33 publications

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“…Yang, et al Virus Research 280 (2020) 197901 NHE3 translocation to stimulate NHE3 activity (Cha and Donowitz, 2008). Moreover, a co-transport relationship exists between SGLT1 and NHE3 under physiological conditions (Coon et al, 2011). In the present study, we found that SGLT1 inhibition via siRNA transfection and treatment with Phlorizin could up-regulate the expression of p-MAP-KAPK-2 and p-Ezrin in the p38MAPK/Akt2 pathway and increase the translocation of NHE3.…”

Section: Discussionsupporting

confidence: 53%

“…Some studies have shown that together, SGLT1 and NHE3 regulate sodium absorption in epithelial cells (Coon et al, 2011); however, it is unclear what a physiological relationship between SGLT1-medated activation of the p38MAPK/Akt2 pathway and regulation of NHE3 translocation. To explore the associated regulatory relationships, we inhibited SGLT1 expression by transfection with siRNAs and treatment with inhibitors.…”

Section: Regulation Of Sglt1 On Nhe3 Translocation In Mock-infected Cmentioning

confidence: 99%

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Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Yang

Song

et al. 2020

Virus Research

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A B S T R A C TTransmissible gastroenteritis virus (TGEV) primarily replicates in intestinal epithelial cells and causes severe damage to host cells, resulting in diarrhea. Surface NHE3 serves as the key regulatory site controlling electroneutral Na + absorption. In this study, our results showed that the surface NHE3 content was significantly reduced following TGEV infection, whereas the total level of protein expression was not significantly changed, and NHE3 activity gradually decreased with prolonged infection time. We then inhibited SGLT1 expression by lentiviral interference and drug inhibition, respectively. Inhibition studies showed that the level of phosphorylation of the downstream key proteins, MAPKAPK-2 and EZRIN, in the SGLT1-mediated p38MAPK/AKt2 signaling pathway was significantly increased. The surface NHE3 expression was also significantly increased, and NHE3 activity was also significantly enhanced. These results demonstrate that a TGEV infection can inhibit NHE3 translocation and attenuates sodium-hydrogen exchange activity via the SGLT1-mediated p38MAPK/AKt2 signaling pathway, affecting cellular electrolyte absorption leading to diarrhea.

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Section: Discussionsupporting

confidence: 53%

Section: Regulation Of Sglt1 On Nhe3 Translocation In Mock-infected Cmentioning

confidence: 99%

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Yang

Song

et al. 2020

Virus Research

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“…Most importantly, glucose fully reversed cholera toxin-induced inhibition of NHE3 activity, thus adding a new dimension to the protective mechanisms of oral rehydration in acute watery diarrhea. Interestingly, another study by Coon et al [9], which also explored the interaction between SGLT1 and NHE3, demonstrated that expression of these two transporters is linked to their function. This was demonstrated in vitro in IEC-18 cells transfected with either NHE3 or SGLT1 siRNA.…”

Section: Nherf Proteins In Nhe3-mediated Na+ Absorptionmentioning

confidence: 99%

“…This was demonstrated in vitro in IEC-18 cells transfected with either NHE3 or SGLT1 siRNA. Expression and function of the two carriers were reciprocally regulated, that is, knockdown of SGLT1 increased NHE3 expression and activity and vice versa [9]. …”

Section: Nherf Proteins In Nhe3-mediated Na+ Absorptionmentioning

confidence: 99%

Small intestinal ion transport

Kiela¹

2012

Current Opinion in Gastroenterology

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Purpose of review In this review, we focus on the recent (March 2010 to September 2011) advances in small intestinal ion transport, with particular emphasis on sodium, chloride, bicarbonate, and calcium transport mechanisms under physiological and pathophysiological conditions. Recent findings Knockout of NHERF1 and NHERF2 allowed translation of the data largely derived from the in-vitro models into a living organism. These studies also expand our knowledge about the complexity of intestinal transporter interactomes, define the role for scaffolding proteins in basal and regulated apical transport, and help identify potential targets for pharmacological approaches. We continue to accumulate novel information about the function and regulation of NHE3 (including its role in regulating paracellular Ca2+ flux), NHE8, as well as about the complexity of the intestinal Cl− and HCO3− transport in health and disease. Summary Thanks to the new genetically engineered mouse models, a significant progress has been made in our understanding of the role of NHERF proteins in regulation of intestinal Na+ absorption. Significant novel data on the coordinated function of bicarbonate, chloride, and sodium transporters contributes to our current views of the integrative physiology of the small intestinal electrolyte transport.

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“…However, how these distinct transport processes may be coordinately regulated to disrupt glucose and NaCl homeostasis in obesity resulting in diabetes and hypertension is not known. (38), was obtained from American Type Culture Collection (ATCC; CRL-1589). Cells were used only between passages 5 and 25 and grown in high-glucose DMEM supplemented with 0.2 U/ml of insulin, 0.5 mM b-hydroxybutyrate, and 10% fetal calf serum and incubated at 37°C with 10% CO 2 in a humidified atmosphere.…”

mentioning

confidence: 99%

Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension

et al. 2019

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During obesity, diabetes and hypertension inevitably coexist and cause innumerable health disparities. In the obesity, diabetes, and hypertension triad (ODHT), deregulation of glucose and NaCl homeostasis, respectively, causes diabetes and hypertension. In the mammalian intestine, glucose is primarily absorbed by Naglucose cotransport 1 (SGLT1) and coupled NaCl by the dual operation of Na‐H exchange 3 (NHE3) and Cl‐HCO3 [down‐regulated in adenoma (DRA) or putative anion transporter 1 (PAT1)] exchange in the brush border membrane (BBM) of villus cells. The basolateral membrane (BLM) Na/K‐ATPase provides the favorable transcellular Na gradient for BBM SGLT1 and NHE3. How these multiple, distinct transport processes may be affected in ODHT is unclear. Here, we show the novel and broad regulation by Na/K‐ATPase of glucose and NaCl absorption in ODHT in multiple species (mice, rats, and humans). In vivo, during obesity inhibition of villus‐cell BLM, Na/K‐ATPase led to compensatory stimulation of BBM SGLT1 and DRA or PAT1, whereas NHE3 was unaffected. Supporting this new cellular adaptive mechanism, direct silencing of BLM Na/K‐ATPase in intestinal epithelial cells resulted in selective stimulation of BBM SGLT1 and DRA or PAT1 but not NHE3. These changes will lead to an increase in glucose absorption, maintenance of traditional coupled NaCl absorption, and a de novo increase in NaCl absorption from the novel coupling of stimulated SGLT1 with DRA or PAT1. Thus, these novel observations provide the pathophysiologic basis for the deregulation of glucose and NaCl homeostasis of diabetes and hypertension, respectively, during obesity. These observations may lead to more efficacious treatment for obesity‐associated diabetes and hypertension.—Palaniappan, B., Arthur, S., Sundaram, V. L., Butts, M., Sundaram, S., Mani, K., Singh, S., Nepal, N., Sundaram, U. Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension. FASEB J. 33, 9323–9333 (2019). http://www.fasebj.org

show abstract

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

Cited by 25 publications

References 33 publications

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Decreased NHE3 activity and trafficking in TGEV-infected IPEC-J2 cells via the SGLT1-mediated P38 MAPK/AKt2 pathway

Small intestinal ion transport

Inhibition of intestinal villus cell Na/K‐ATPase mediates altered glucose and NaCl absorption in obesity‐associated diabetes and hypertension

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