Eintrag weiter verarbeiten
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange
Gespeichert in:
| Zeitschriftentitel: | American Journal of Physiology-Renal Physiology |
|---|---|
| Personen und Körperschaften: | , , |
| In: | American Journal of Physiology-Renal Physiology, 305, 2013, 4, S. F451-F462 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Physiological Society
|
| Schlagwörter: |
| author_facet |
Watts, Bruns A. George, Thampi Good, David W. Watts, Bruns A. George, Thampi Good, David W. |
|---|---|
| author |
Watts, Bruns A. George, Thampi Good, David W. |
| spellingShingle |
Watts, Bruns A. George, Thampi Good, David W. American Journal of Physiology-Renal Physiology Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange Physiology |
| author_sort |
watts, bruns a. |
| spelling |
Watts, Bruns A. George, Thampi Good, David W. 1931-857X 1522-1466 American Physiological Society Physiology http://dx.doi.org/10.1152/ajprenal.00102.2013 <jats:p>Sepsis and endotoxemia induce defects in renal tubule function, but the mechanisms are poorly understood. Recently, we demonstrated that lipopolysaccharide (LPS) inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption through ERK-dependent inhibition of the apical Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchanger NHE3. Here, we examined the mechanisms of inhibition by lumen LPS. Adding LPS to the lumen decreased HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption were eliminated in MTALs from TLR4<jats:sup>−/−</jats:sup>and MyD88<jats:sup>−/−</jats:sup>mice but preserved in tubules lacking Trif or CD14. Inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption by lumen LPS was eliminated under conditions that inhibit basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange and prevent inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption mediated through NHE1. Lumen LPS decreased basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange activity through PI3K. We conclude that lumen LPS inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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.</jats:p> Lumen LPS inhibits HCO<sub>3</sub><sup>−</sup>absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na<sup>+</sup>/H<sup>+</sup>exchange American Journal of Physiology-Renal Physiology |
| doi_str_mv |
10.1152/ajprenal.00102.2013 |
| facet_avail |
Online Free |
| finc_class_facet |
Biologie |
| format |
ElectronicArticle |
| fullrecord |
blob:ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE1Mi9hanByZW5hbC4wMDEwMi4yMDEz |
| id |
ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE1Mi9hanByZW5hbC4wMDEwMi4yMDEz |
| institution |
DE-Brt1 DE-D161 DE-Zwi2 DE-Gla1 DE-Zi4 DE-15 DE-Pl11 DE-Rs1 DE-105 DE-14 DE-Ch1 DE-L229 DE-D275 DE-Bn3 |
| imprint |
American Physiological Society, 2013 |
| imprint_str_mv |
American Physiological Society, 2013 |
| issn |
1931-857X 1522-1466 |
| issn_str_mv |
1931-857X 1522-1466 |
| language |
English |
| mega_collection |
American Physiological Society (CrossRef) |
| match_str |
watts2013lumenlpsinhibitshco3absorptioninthemedullarythickascendinglimbthroughtlr4pi3kaktmtordependentinhibitionofbasolateralnahexchange |
| publishDateSort |
2013 |
| publisher |
American Physiological Society |
| recordtype |
ai |
| record_format |
ai |
| series |
American Journal of Physiology-Renal Physiology |
| source_id |
49 |
| title |
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_unstemmed |
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_full |
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_fullStr |
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_full_unstemmed |
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_short |
Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_sort |
lumen lps inhibits hco<sub>3</sub><sup>−</sup>absorption in the medullary thick ascending limb through tlr4-pi3k-akt-mtor-dependent inhibition of basolateral na<sup>+</sup>/h<sup>+</sup>exchange |
| topic |
Physiology |
| url |
http://dx.doi.org/10.1152/ajprenal.00102.2013 |
| publishDate |
2013 |
| physical |
F451-F462 |
| description |
<jats:p>Sepsis and endotoxemia induce defects in renal tubule function, but the mechanisms are poorly understood. Recently, we demonstrated that lipopolysaccharide (LPS) inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption through ERK-dependent inhibition of the apical Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchanger NHE3. Here, we examined the mechanisms of inhibition by lumen LPS. Adding LPS to the lumen decreased HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption were eliminated in MTALs from TLR4<jats:sup>−/−</jats:sup>and MyD88<jats:sup>−/−</jats:sup>mice but preserved in tubules lacking Trif or CD14. Inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption by lumen LPS was eliminated under conditions that inhibit basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange and prevent inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption mediated through NHE1. Lumen LPS decreased basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange activity through PI3K. We conclude that lumen LPS inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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.</jats:p> |
| container_issue |
4 |
| container_start_page |
0 |
| container_title |
American Journal of Physiology-Renal Physiology |
| container_volume |
305 |
| format_de105 |
Article, E-Article |
| format_de14 |
Article, E-Article |
| format_de15 |
Article, E-Article |
| format_de520 |
Article, E-Article |
| format_de540 |
Article, E-Article |
| format_dech1 |
Article, E-Article |
| format_ded117 |
Article, E-Article |
| format_degla1 |
E-Article |
| format_del152 |
Buch |
| format_del189 |
Article, E-Article |
| format_dezi4 |
Article |
| format_dezwi2 |
Article, E-Article |
| format_finc |
Article, E-Article |
| format_nrw |
Article, E-Article |
| _version_ |
1792335053800341505 |
| geogr_code |
not assigned |
| last_indexed |
2024-03-01T14:38:27.014Z |
| geogr_code_person |
not assigned |
| openURL |
url_ver=Z39.88-2004&ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fvufind.svn.sourceforge.net%3Agenerator&rft.title=Lumen+LPS+inhibits+HCO3%E2%88%92absorption+in+the+medullary+thick+ascending+limb+through+TLR4-PI3K-Akt-mTOR-dependent+inhibition+of+basolateral+Na%2B%2FH%2Bexchange&rft.date=2013-08-15&genre=article&issn=1522-1466&volume=305&issue=4&pages=F451-F462&jtitle=American+Journal+of+Physiology-Renal+Physiology&atitle=Lumen+LPS+inhibits+HCO%3Csub%3E3%3C%2Fsub%3E%3Csup%3E%E2%88%92%3C%2Fsup%3Eabsorption+in+the+medullary+thick+ascending+limb+through+TLR4-PI3K-Akt-mTOR-dependent+inhibition+of+basolateral+Na%3Csup%3E%2B%3C%2Fsup%3E%2FH%3Csup%3E%2B%3C%2Fsup%3Eexchange&aulast=Good&aufirst=David+W.&rft_id=info%3Adoi%2F10.1152%2Fajprenal.00102.2013&rft.language%5B0%5D=eng |
| SOLR | |
| _version_ | 1792335053800341505 |
| author | Watts, Bruns A., George, Thampi, Good, David W. |
| author_facet | Watts, Bruns A., George, Thampi, Good, David W., Watts, Bruns A., George, Thampi, Good, David W. |
| author_sort | watts, bruns a. |
| container_issue | 4 |
| container_start_page | 0 |
| container_title | American Journal of Physiology-Renal Physiology |
| container_volume | 305 |
| description | <jats:p>Sepsis and endotoxemia induce defects in renal tubule function, but the mechanisms are poorly understood. Recently, we demonstrated that lipopolysaccharide (LPS) inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption through ERK-dependent inhibition of the apical Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchanger NHE3. Here, we examined the mechanisms of inhibition by lumen LPS. Adding LPS to the lumen decreased HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption were eliminated in MTALs from TLR4<jats:sup>−/−</jats:sup>and MyD88<jats:sup>−/−</jats:sup>mice but preserved in tubules lacking Trif or CD14. Inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption by lumen LPS was eliminated under conditions that inhibit basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange and prevent inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption mediated through NHE1. Lumen LPS decreased basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange activity through PI3K. We conclude that lumen LPS inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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.</jats:p> |
| doi_str_mv | 10.1152/ajprenal.00102.2013 |
| facet_avail | Online, Free |
| finc_class_facet | Biologie |
| format | ElectronicArticle |
| format_de105 | Article, E-Article |
| format_de14 | Article, E-Article |
| format_de15 | Article, E-Article |
| format_de520 | Article, E-Article |
| format_de540 | Article, E-Article |
| format_dech1 | Article, E-Article |
| format_ded117 | Article, E-Article |
| format_degla1 | E-Article |
| format_del152 | Buch |
| format_del189 | Article, E-Article |
| format_dezi4 | Article |
| format_dezwi2 | Article, E-Article |
| format_finc | Article, E-Article |
| format_nrw | Article, E-Article |
| geogr_code | not assigned |
| geogr_code_person | not assigned |
| id | ai-49-aHR0cDovL2R4LmRvaS5vcmcvMTAuMTE1Mi9hanByZW5hbC4wMDEwMi4yMDEz |
| imprint | American Physiological Society, 2013 |
| imprint_str_mv | American Physiological Society, 2013 |
| institution | DE-Brt1, DE-D161, DE-Zwi2, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3 |
| issn | 1931-857X, 1522-1466 |
| issn_str_mv | 1931-857X, 1522-1466 |
| language | English |
| last_indexed | 2024-03-01T14:38:27.014Z |
| match_str | watts2013lumenlpsinhibitshco3absorptioninthemedullarythickascendinglimbthroughtlr4pi3kaktmtordependentinhibitionofbasolateralnahexchange |
| mega_collection | American Physiological Society (CrossRef) |
| physical | F451-F462 |
| publishDate | 2013 |
| publishDateSort | 2013 |
| publisher | American Physiological Society |
| record_format | ai |
| recordtype | ai |
| series | American Journal of Physiology-Renal Physiology |
| source_id | 49 |
| spelling | Watts, Bruns A. George, Thampi Good, David W. 1931-857X 1522-1466 American Physiological Society Physiology http://dx.doi.org/10.1152/ajprenal.00102.2013 <jats:p>Sepsis and endotoxemia induce defects in renal tubule function, but the mechanisms are poorly understood. Recently, we demonstrated that lipopolysaccharide (LPS) inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption through ERK-dependent inhibition of the apical Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchanger NHE3. Here, we examined the mechanisms of inhibition by lumen LPS. Adding LPS to the lumen decreased HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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 HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption were eliminated in MTALs from TLR4<jats:sup>−/−</jats:sup>and MyD88<jats:sup>−/−</jats:sup>mice but preserved in tubules lacking Trif or CD14. Inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption by lumen LPS was eliminated under conditions that inhibit basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange and prevent inhibition of HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>absorption mediated through NHE1. Lumen LPS decreased basolateral Na<jats:sup>+</jats:sup>/H<jats:sup>+</jats:sup>exchange activity through PI3K. We conclude that lumen LPS inhibits HCO<jats:sub>3</jats:sub><jats:sup>−</jats:sup>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.</jats:p> Lumen LPS inhibits HCO<sub>3</sub><sup>−</sup>absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na<sup>+</sup>/H<sup>+</sup>exchange American Journal of Physiology-Renal Physiology |
| spellingShingle | Watts, Bruns A., George, Thampi, Good, David W., American Journal of Physiology-Renal Physiology, Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange, Physiology |
| title | Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_full | Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_fullStr | Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_full_unstemmed | Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_short | Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| title_sort | lumen lps inhibits hco<sub>3</sub><sup>−</sup>absorption in the medullary thick ascending limb through tlr4-pi3k-akt-mtor-dependent inhibition of basolateral na<sup>+</sup>/h<sup>+</sup>exchange |
| title_unstemmed | Lumen LPS inhibits HCO3−absorption in the medullary thick ascending limb through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+exchange |
| topic | Physiology |
| url | http://dx.doi.org/10.1152/ajprenal.00102.2013 |