Endotoxin differentially modulates the basolateral and apical sodium/proton exchangers (NHE) in enterocytes

Çetin, Selma; Dunklebarger, Joshua; Li, Jun; Boyle, Patricia; Ergün, Orkan; Qureshi, Faisal; Ford, Henri R.; Upperman, Jeffrey S.; Watkins, Simon C.; Hackam, David J.

doi:10.1016/j.surg.2004.05.013

Cited by 30 publications

(23 citation statements)

References 24 publications

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“…These results are consistent with our previous studies demonstrating that NGF inhibits MTAL HCO 3 Ϫ absorption through PI3K-mTOR-dependent inhibition of NHE1 (28,32). NHE1 has been identified as a target for LPS-induced regulation in other cell systems and has been ascribed a role in a variety of immunoregulatory cell responses, including cytokine and chemokine production, migration, survival, and phagocytosis (5,8,14,22,58,65). We show that NHE1 is a downstream target of LPS-induced TLR4 signaling in renal tubule cells and that LPS impairs the absorptive function of the MTAL through inhibition of this exchanger.…”

Section: Lpssupporting

confidence: 93%

“…Thus it is conceivable that lumen LPS inhibits MTAL HCO 3 Ϫ absorption through PI3K-mTOR-mediated inhibition of NHE1. LPS has been shown to modulate NHE1 in other cell systems, including immune cells, endothelial cells, and intestinal epithelial cells (5,8,14,58,65). Whether NHE1 is regulated by LPS or is a downstream target of TLR4 signaling in renal tubules has not been determined.…”

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confidence: 99%

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Lumen LPS inhibits HCO₃⁻absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na⁺/H⁺exchange

Watts

George

Good

2013

American Journal of Physiology-Renal Physiology

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Sepsis and endotoxemia induce defects in renal tubule function, but the mechanisms are poorly understood. Recently, we demonstrated that lipopolysaccharide (LPS) inhibits HCO3(-) absorption in the medullary thick ascending limb (MTAL) through activation of different Toll-like receptor 4 (TLR4) signaling pathways in the basolateral and apical membranes. Basolateral LPS inhibits HCO3(-) absorption through ERK-dependent inhibition of the apical Na(+)/H(+) exchanger NHE3. Here, we examined the mechanisms of inhibition by lumen LPS. Adding LPS to the lumen decreased HCO3(-) absorption by 29% in rat and mouse MTALs perfused in vitro. Inhibitors of phosphoinositide 3-kinase (PI3K) or its effectors Akt and mammalian target of rapamycin (mTOR) eliminated inhibition of HCO3(-) absorption by lumen LPS but had no effect on inhibition by bath LPS. Exposure to LPS for 15 min induced increases in phosphorylation of Akt and mTOR in microdissected MTALs that were blocked by wortmannin, consistent with activation of Akt and mTOR downstream of PI3K. The effects of lumen LPS to activate Akt and inhibit HCO3(-) absorption were eliminated in MTALs from TLR4(-/-) and MyD88(-/-) mice but preserved in tubules lacking Trif or CD14. Inhibition of HCO3(-) absorption by lumen LPS was eliminated under conditions that inhibit basolateral Na(+)/H(+) exchange and prevent inhibition of HCO3(-) absorption mediated through NHE1. Lumen LPS decreased basolateral Na(+)/H(+) exchange activity through PI3K. We conclude that lumen LPS inhibits HCO3(-) absorption in the MTAL through TLR4/MyD88-dependent activation of a PI3K-Akt-mTOR pathway coupled to inhibition of NHE1. Molecular components of the TLR4-PI3K-mTOR pathway represent potential therapeutic targets for sepsis-induced renal tubule dysfunction.

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Section: Lpssupporting

confidence: 93%

mentioning

confidence: 99%

Lumen LPS inhibits HCO₃⁻absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na⁺/H⁺exchange

Watts

George

Good

2013

American Journal of Physiology-Renal Physiology

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“…Necrotizing enterocolitis is the most lethal disease that affects the gastrointestinal tract, most commonly the terminal ileum and proximal colon of premature infants, that is characterized by edema, ischemia, intestinal necrosis, and systemic sepsis [1,3,4,11,12]. Despite massive number of research, exact mechanisms governing the cascade leading to the disease still remain undetermined.…”

Section: Discussionmentioning

confidence: 99%

Enteral resveratrol supplementation attenuates intestinal epithelial inducible nitric oxide synthase activity and mucosal damage in experimental necrotizing enterocolitis

Ergün

Öktem

et al. 2007

Journal of Pediatric Surgery

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“…J774 macrophages were obtained from the American Type Culture Collection (ATCC, Manassas, VA) and maintained in DMEM supplemented with 10% fetal bovine serum, 1% glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin at 37°C in a 5% CO 2 atmosphere as described (22). Intestinal epithelial cell (IEC)-6 cells were also obtained from the ATCC and maintained in DMEM supplemented with 5% fetal bovine serum, 1% glutamine, 100 units/ml penicillin, 100 g/ml streptomycin, and 0.1% insulin at 37°C in a 5% CO 2 atmosphere as described (7). Antibodies against phosphorylated Cx43 were from Chemicon (Temecula, CA); CD45 was from Abcam (Cambridge, MA).…”

Section: Methodsmentioning

confidence: 99%

Activated macrophages inhibit enterocyte gap junctions via the release of nitric oxide

Dai

Rippel

Leaphart

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Enterocytes exist in close association with tissue macrophages, whose activation during inflammatory processes leads to the release of nitric oxide (NO). Repair from mucosal injury requires the migration of enterocytes into the mucosal defect, a process that requires connexin43 (Cx43)-mediated gap junction communication between adjacent enterocytes. Enterocyte migration is inhibited during inflammatory conditions including necrotizing enterocolitis, in part, through impaired gap junction communication. We now hypothesize that activated macrophages inhibit gap junctions of adjacent enterocytes and seek to determine whether NO release from macrophages was involved. Using a coculture system of enterocytes and macrophages, we now demonstrate that "activation" of macrophages with lipopolysaccharide and interferon reduces the phosphorylation of Cx43 in adjacent enterocytes, an event known to inhibit gap junction communication. The effects of macrophages on enterocyte gap junctions could be reversed by treatment of macrophages with the inducible nitric oxide synthase (iNOS) inhibitor l-Lysine omega-acetamidine hydrochloride (l-NIL) and by incubation with macrophages from iNOS(-/-) mice, implicating NO in the process. Activated macrophages also caused a NO-dependent redistribution of connexin43 in adjacent enterocytes from the cell surface to an intracellular location, further suggesting NO release may inhibit gap junction function. Treatment of enterocytes with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) markedly inhibited gap junction communication as determined using single cell microinjection of the gap junction tracer Lucifer yellow. Strikingly, activated macrophages inhibited enterocyte migration into a scraped wound, which was reversed by l-NIL pretreatment. These results implicate enterocyte gap junctions as a target of the NO-mediated effects of macrophages during intestinal inflammation, particularly where enterocyte migration is impaired.

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Endotoxin differentially modulates the basolateral and apical sodium/proton exchangers (NHE) in enterocytes

Cited by 30 publications

References 24 publications

Lumen LPS inhibits HCO₃⁻absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na⁺/H⁺exchange

Lumen LPS inhibits HCO₃⁻absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na⁺/H⁺exchange

Enteral resveratrol supplementation attenuates intestinal epithelial inducible nitric oxide synthase activity and mucosal damage in experimental necrotizing enterocolitis

Activated macrophages inhibit enterocyte gap junctions via the release of nitric oxide

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Endotoxin differentially modulates the basolateral and apical sodium/proton exchangers (NHE) in enterocytes

Cited by 30 publications

References 24 publications

Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange

Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange

Enteral resveratrol supplementation attenuates intestinal epithelial inducible nitric oxide synthase activity and mucosal damage in experimental necrotizing enterocolitis

Activated macrophages inhibit enterocyte gap junctions via the release of nitric oxide

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Lumen LPS inhibits HCO₃⁻absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na⁺/H⁺exchange

Lumen LPS inhibits HCO₃⁻absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na⁺/H⁺exchange