Role of TLR4 signaling in the nephrotoxicity of Heme and heme proteins

Karl A. Nath, John D Belcher, Meryl C. Nath, Joseph P. Grande, Anthony J. Croatt, Allan W. Ackerman, Zvonimir S. Katusic, Gregory M Vercellotti

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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-κB 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 proteininduced acute kidney injury (AKI), findings corroborated by studies in TLR4 +/+ and TLR4 -/- mice. We conclude that 1) acute hememediated 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 glycerolinduced, 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.

Original languageEnglish (US)
Pages (from-to)F906-F914
JournalAmerican Journal of Physiology - Renal Physiology
Volume314
Issue number5
DOIs
StatePublished - Jan 1 2018

Fingerprint

Hemeproteins
Toll-Like Receptor 4
Heme
Acute Kidney Injury
Kidney
Chemokine CCL2
Renal Circulation
Glycerol
Anti-Inflammatory Agents
Heme Oxygenase-1
Poisons
Wounds and Injuries
Vasoconstriction
Intravenous Administration
Genes

Keywords

  • Heme
  • Heme oxygenase-1
  • MCP-1
  • Sickle cell disease
  • TLR4 receptor

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

Cite this

Role of TLR4 signaling in the nephrotoxicity of Heme and heme proteins. / Nath, Karl A.; Belcher, John D; Nath, Meryl C.; Grande, Joseph P.; Croatt, Anthony J.; Ackerman, Allan W.; Katusic, Zvonimir S.; Vercellotti, Gregory M.

In: American Journal of Physiology - Renal Physiology, Vol. 314, No. 5, 01.01.2018, p. F906-F914.

Research output: Contribution to journalArticle

Nath, Karl A. ; Belcher, John D ; Nath, Meryl C. ; Grande, Joseph P. ; Croatt, Anthony J. ; Ackerman, Allan W. ; Katusic, Zvonimir S. ; Vercellotti, Gregory M. / Role of TLR4 signaling in the nephrotoxicity of Heme and heme proteins. In: American Journal of Physiology - Renal Physiology. 2018 ; Vol. 314, No. 5. pp. F906-F914.
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