PMID- 23698118
OWN - NLM
STAT- MEDLINE
DCOM- 20131231
LR  - 20220311
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 305
IP  - 4
DP  - 2013 Aug 15
TI  - Lumen LPS inhibits HCO3(-) absorption in the medullary thick ascending limb 
      through TLR4-PI3K-Akt-mTOR-dependent inhibition of basolateral Na+/H+ exchange.
PG  - F451-62
LID - 10.1152/ajprenal.00102.2013 [doi]
AB  - 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.
FAU - Watts, Bruns A 3rd
AU  - Watts BA 3rd
AD  - Div. of Nephrology, 4.200 John Sealy Annex, The Univ. of Texas Medical Branch, 
      301 Univ. Blvd., Galveston, TX 77555-0562. dgood@utmb.edu.
FAU - George, Thampi
AU  - George T
FAU - Good, David W
AU  - Good DW
LA  - eng
GR  - R01 DK038217/DK/NIDDK NIH HHS/United States
GR  - DK-038217/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130522
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Bicarbonates)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Protons)
RN  - 0 (Slc9a1 protein, mouse)
RN  - 0 (Slc9a1 protein, rat)
RN  - 0 (Sodium-Hydrogen Exchanger 1)
RN  - 0 (Sodium-Hydrogen Exchangers)
RN  - 0 (Toll-Like Receptor 4)
RN  - 9NEZ333N27 (Sodium)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Bicarbonates/metabolism
MH  - Cation Transport Proteins/*metabolism
MH  - Immunoblotting
MH  - Kidney Tubules/drug effects/*metabolism
MH  - Lipopolysaccharides/*immunology
MH  - Loop of Henle/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Microscopy, Confocal
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Protons
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Sodium/metabolism
MH  - Sodium-Hydrogen Exchanger 1
MH  - Sodium-Hydrogen Exchangers/*metabolism
MH  - TOR Serine-Threonine Kinases/drug effects/*metabolism
MH  - Toll-Like Receptor 4/*metabolism
PMC - PMC3891256
OTO - NOTNLM
OT  - Na+/H+ exchange
OT  - TLR4 signaling
OT  - acid-base balance
OT  - kidney
OT  - sepsis
EDAT- 2013/05/24 06:00
MHDA- 2014/01/01 06:00
PMCR- 2014/08/15
CRDT- 2013/05/24 06:00
PHST- 2013/05/24 06:00 [entrez]
PHST- 2013/05/24 06:00 [pubmed]
PHST- 2014/01/01 06:00 [medline]
PHST- 2014/08/15 00:00 [pmc-release]
AID - ajprenal.00102.2013 [pii]
AID - F-00102-2013 [pii]
AID - 10.1152/ajprenal.00102.2013 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2013 Aug 15;305(4):F451-62. doi: 
      10.1152/ajprenal.00102.2013. Epub 2013 May 22.