Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury

Department of Internal Medicine Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8856, USA.
Kidney International (Impact Factor: 8.56). 10/2010; 79(3):288-99. DOI: 10.1038/ki.2010.381
Source: PubMed


Ischemic acute kidney injury (AKI) triggers an inflammatory response which exacerbates injury that requires increased expression of endothelial adhesion molecules. To study this further, we used in situ hybridization, immunohistology, and isolated endothelial cells, and found increased Toll-like receptor 4 (TLR4) expression on endothelial cells of the vasa rectae of the inner stripe of the outer medulla of the kidney 4 h after reperfusion. This increase was probably due to reactive oxygen species, known to be generated early during ischemic AKI, because the addition of hydrogen peroxide increased TLR4 expression in MS1 microvascular endothelial cells in vitro. Endothelial TLR4 may regulate adhesion molecule (CD54 and CD62E) expression as they were increased on endothelia of wild-type but not TLR4 knockout mice in vivo. Further, the addition of high-mobility group protein B1, a TLR4 ligand released by injured cells, increased adhesion molecule expression on endothelia isolated from wild-type but not TLR4 knockout mice. TLR4 was localized to proximal tubules in the cortex and outer medulla after 24 h of reperfusion. Thus, at least two different cell types express TLR4, each of which contributes to renal injury by temporally different mechanisms during ischemic AKI.

16 Reads
  • Source
    • "In recent years, the role of innate immune receptor–TLRs in renal diseases has been increasingly recognized [11] [12]. Various studies have provided evidence that link TLR4 and renal cell injury in DN [13] [14], the details are still under active consideration [15] [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like Receptor 4 (TLR4) may play an important role in the pathogenesis of diabetic nephropathy (DN). In this study, We observed the TLR4 signal and the release of inflammation factors after angiotensin II (Ang II) stimulation in rat mesangial cells (MCs) under high glucose conditions, this revealed the innate immune mechanism of injury by Ang II in DN. Our data showed that TLR4 and MyD88 were up-regulated significantly in high glucose and AngII-induced MCs; meanwhile, NF-κB as well as MCP-1, IL-6 were also highly expressed. In cells that were transfected with TLR4 SiRNA,the parameters were greatly inhibited; similar effects were detected in cells that were treated with Irbesartan. We concluded that Ang II synergized with high glucose in the release of pro-inflammatory factors mainly through the upregulation of TLR4 signaling in MCs, Cross-talk between Ang II and TLR4 contributed to the MC inflammatory injury under high glucose conditions. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 02/2015; 459(2). DOI:10.1016/j.bbrc.2015.02.096 · 2.30 Impact Factor
  • Source
    • "Extensive research has been performed in the last decades to elucidate the molecular mechanisms underlying acute kidney injury (AKI). To date we know that TLRs are involved in the pathogenesis of ischemia and reperfusion-related inflammation and AKI [31], [32], [33], [34], [35]. However, TLR-3 has not been described in renal IR so far. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acute kidney injury (AKI) is one of the most important complications in hospitalized patients and its pathomechanisms are not completely elucidated. We hypothesize that signaling via toll-like receptor (TLR)-3, a receptor that is activated upon binding of double-stranded nucleotides, might play a crucial role in the pathogenesis of AKI following ischemia and reperfusion (IR). Male adult C57Bl6 wild-type (wt) mice and TLR-3 knock-out (-/-) mice were subjected to 30 minutes bilateral selective clamping of the renal artery followed by reperfusion for 30 min 2.5h and 23.5 hours or subjected to sham procedures. TLR-3 down-stream signaling was activated already within 3 h of ischemia and reperfusion in post-ischemic kidneys of wt mice lead to impaired blood perfusion followed by a strong pro-inflammatory response with significant neutrophil invasion. In contrast, this effect was absent in TLR-3-/- mice. Moreover, the quick TLR-3 activation resulted in kidney damage that was histomorphologically associated with significantly increased apoptosis and necrosis rates in renal tubules of wt mice. This finding was confirmed by increased kidney injury marker NGAL in wt mice and a better preserved renal perfusion after IR in TLR-3-/- mice than wt mice. Overall, the absence of TLR-3 is associated with lower cumulative kidney damage and maintained renal blood perfusion within the first 24 hours of reperfusion. Thus, we conclude that TLR-3 seems to participate in the pathogenesis of early acute kidney injury.
    PLoS ONE 04/2014; 9(4):e94366. DOI:10.1371/journal.pone.0094366 · 3.23 Impact Factor
  • Source
    • "Consistently, the increased TLR7 was demonstrated in the caspase-3 siRNA preserved auto-transplant kidneys in this study, accompanied by MyD88 activation, which led to the activation and nuclear translocation of NF-κB and c-Jun. As a result, the production of IFN-α, IFN-β and IFN-γ, as well as inflammatory cytokines TNF-α, IL-1β and IL-6, were remarkably increased and auto-transplant kidney structure was more severely damaged [6,17-20]. These cascade responses more liked were due to a systemic feedback post 48-h transplantation, rather than persistent actions initiated by caspase-3 siRNA in 24-h cold preservation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The naked caspase-3 small interfering RNA (siRNA) infused into the renal artery during cold preservation was effective, but did not protect auto-transplant porcine kidneys with increased inflammation and apoptosis in our previous study. The mechanisms involved, in particular, whether siRNA or complementary systemic feedback eliciting innate immune responses are worthy to be further investigated. The protein and mRNA expression of innate immunity-related molecules were detected by western blotting and quantitative PCR in the tissues previously collected from 48 h auto-transplant kidneys. The donor kidneys were retrieved from mini pigs and cold preserved by University of Wisconsin solution with/without 0.3 mg caspase-3 siRNA for 24 h. The protein level of Toll like receptor (TLR) 3, TLR7, and their main adapters, TRIF and MyD88, was up-regulated in the siRNA preserved auto-transplant kidneys. The mRNA level of NF-kappaB and c-Jun was increased, as well as pro-inflammatory cytokines, including IL-1beta, IL-6, TNF-alpha and interferon (IFN)-alpha, beta and gamma. In addition, the non-TLR RNA sensor PKR protein, but not RIG1, was also increased in the siRNA preserved auto-transplant kidneys. The activation of innate immunity with amplified inflammatory responses in the caspase-3 siRNA preserved auto-transplant kidneys are associated with increased TLR3, TLR7 and PKR, which might be due to complementary systemic feedback, although persistent actions initiated by short-acting caspase-3 siRNA cannot be completely ruled out. These results provided valuable evidence to guide future siRNA design and pre-clinic studies.
    Journal of Translational Medicine 09/2013; 11(1):210. DOI:10.1186/1479-5876-11-210 · 3.93 Impact Factor
Show more

Similar Publications

Preview (2 Sources)

16 Reads
Available from