PMID- 28978536
OWN - NLM
STAT- MEDLINE
DCOM- 20190903
LR  - 20231129
IS  - 1522-1466 (Electronic)
IS  - 1931-857X (Print)
IS  - 1522-1466 (Linking)
VI  - 314
IP  - 5
DP  - 2018 May 1
TI  - Role of TLR4 signaling in the nephrotoxicity of heme and heme proteins.
PG  - F906-F914
LID - 10.1152/ajprenal.00432.2017 [doi]
AB  - Destabilized heme proteins release heme, and free heme is toxic. Heme is now 
      recognized as an agonist for the Toll-like receptor-4 (TLR4) receptor. This study 
      examined whether the TLR4 receptor mediates the nephrotoxicity of heme, 
      specifically, the effects of heme on renal blood flow and inflammatory responses. 
      We blocked TLR4 signaling by the specific antagonist TAK-242. Intravenous 
      administration of heme to mice promptly reduced renal blood flow, an effect 
      attenuated by TAK-242. In vitro, TAK-242 reduced heme-elicited activation of 
      NF-kappaB and its downstream gene monocyte chemoattractant protein-1(MCP-1); in 
      contrast, TAK-242 failed to reduce heme-induced activation of the 
      anti-inflammatory transcription factor Nrf2 and its downstream gene heme 
      oxygenase-1 (HO-1). TAK-242 did not reduce heme-induced renal MCP-1 upregulation 
      in vivo. TAK-242 did not reduce dysfunction and histological injury in the 
      glycerol model of heme protein-induced acute kidney injury (AKI), findings 
      corroborated by studies in TLR4(+/+) and TLR4(-/-) mice. We conclude that 1) 
      acute heme-mediated renal vasoconstriction occurs through TLR4 signaling; 2) 
      proinflammatory effects of heme in renal epithelial cells involve TLR4 signaling, 
      whereas the anti-inflammatory effects of heme do not; 3) TLR4 signaling does not 
      mediate the proinflammatory effects of heme in the kidney; and 4) major 
      mechanisms underlying glycerol-induced, heme protein-mediated AKI do not involve 
      TLR4 signaling. These findings in the glycerol model are in stark contrast with 
      findings in virtually all other AKI models studied to date and emphasize the 
      importance of TLR4-independent pathways of heme protein-mediated injury in this 
      model. Finally, these studies urge caution when using observations derived in 
      vitro to predict what occurs in vivo.
FAU - Nath, Karl A
AU  - Nath KA
AD  - Division of Nephrology and Hypertension, Mayo Clinic , Rochester, Minnesota.
FAU - Belcher, John D
AU  - Belcher JD
AD  - Division of Hematology, Oncology and Transplantation, University of Minnesota , 
      Minneapolis, Minnesota.
FAU - Nath, Meryl C
AU  - Nath MC
AD  - Department of Pathology, Mayo Clinic , Rochester, Minnesota.
FAU - Grande, Joseph P
AU  - Grande JP
AD  - Department of Pathology, Mayo Clinic , Rochester, Minnesota.
FAU - Croatt, Anthony J
AU  - Croatt AJ
AD  - Division of Nephrology and Hypertension, Mayo Clinic , Rochester, Minnesota.
FAU - Ackerman, Allan W
AU  - Ackerman AW
AD  - Division of Nephrology and Hypertension, Mayo Clinic , Rochester, Minnesota.
FAU - Katusic, Zvonimir S
AU  - Katusic ZS
AD  - Department of Anesthesiology, Mayo Clinic , Rochester, Minnesota.
FAU - Vercellotti, Gregory M
AU  - Vercellotti GM
AD  - Division of Hematology, Oncology and Transplantation, University of Minnesota , 
      Minneapolis, Minnesota.
LA  - eng
GR  - R01 DK047060/DK/NIDDK NIH HHS/United States
GR  - R01 HL114567/HL/NHLBI NIH HHS/United States
GR  - R37 DK047060/DK/NIDDK NIH HHS/United States
GR  - Z01 AI000911/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20171004
PL  - United States
TA  - Am J Physiol Renal Physiol
JT  - American journal of physiology. Renal physiology
JID - 100901990
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (NF-kappa B)
RN  - 0 (Sulfonamides)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Tlr4 protein, rat)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate)
RN  - 743LRP9S7N (Hemin)
RN  - PDC6A3C0OX (Glycerol)
SB  - IM
MH  - Acute Kidney Injury/chemically induced/*metabolism/pathology/prevention & control
MH  - Animals
MH  - Cell Line
MH  - Chemokine CCL2/metabolism
MH  - Disease Models, Animal
MH  - Epithelial Cells/drug effects/*metabolism/pathology
MH  - Glycerol
MH  - *Hemin
MH  - Kidney/*blood supply/drug effects/*metabolism/pathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-kappa B/metabolism
MH  - Rats
MH  - *Renal Circulation/drug effects
MH  - *Signal Transduction/drug effects
MH  - Sulfonamides/pharmacology
MH  - Toll-Like Receptor 4/*antagonists & inhibitors/deficiency/genetics/*metabolism
MH  - *Vasoconstriction/drug effects
PMC - PMC6031913
OTO - NOTNLM
OT  - MCP-1
OT  - TLR4 receptor
OT  - heme
OT  - heme oxygenase-1
OT  - sickle cell disease
EDAT- 2017/10/06 06:00
MHDA- 2019/09/04 06:00
PMCR- 2019/05/01
CRDT- 2017/10/06 06:00
PHST- 2017/10/06 06:00 [pubmed]
PHST- 2019/09/04 06:00 [medline]
PHST- 2017/10/06 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - ajprenal.00432.2017 [pii]
AID - F-00432-2017 [pii]
AID - 10.1152/ajprenal.00432.2017 [doi]
PST - ppublish
SO  - Am J Physiol Renal Physiol. 2018 May 1;314(5):F906-F914. doi: 
      10.1152/ajprenal.00432.2017. Epub 2017 Oct 4.