RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

Dessing, Mark C.; Pulskens, Wilco P.; Teske, Gwendoline J. D.; Butter, Loes M.; Poll, Tom van der; Yang, Huan; Tracey, Kevin J.; Nawroth, Peter P.; Bierhaus, Angelika; Florquin, Sandrine; Leemans, Jaklien C.

doi:10.1159/000334251

Cited by 20 publications

(11 citation statements)

References 68 publications

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“…Whereas TLR2 and TLR4 are key mediators of kidney IRI, 3,4 RAGE is known not to be significantly involved. 17 Here we confirmed previous finding that both TLR2 and TLR4 mRNA are upregulated in WT mice subjected to kidney IRI. Comparable upregulation of TLR2 was also evident in HMGB1-presensitized mice; however, TLR4 upregulation was less pronounced.…”

Section: Discussionsupporting

confidence: 92%

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Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia–reperfusion injury in mice

Steenstra

Boer

et al. 2014

Kidney International

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A preconditioning effect occurs when exposure to a nonharmful quantity of a mediator of injury provides protection against injury upon subsequent reexposure. High-mobility group box 1 (HMGB1) protein, an endogenous ligand for Toll-like receptor (TLR) 4, is a TLR4-dependent mediator of kidney ischemia-reperfusion injury. Here we determined whether preconditioning with recombinant HMGB1 can block kidney ischemia-reperfusion injury, whether this effect is TLR4 dependent and, if so, how preconditioning downregulates TLR signaling. Wild-type mice pretreated with rHMGB1 before ischemia were protected against kidney ischemia-reperfusion injury, indicated by lower serum creatinine, less tubular damage, less tubulointerstitial neutrophil and macrophage infiltration, and less tubular epithelial cell apoptosis versus control mice. Gene expression of TLR-downstream cytokines and chemokines in ischemia-reperfusion injury kidney were also significantly reduced. While TLR4 and TLR2 knockout mice were protected against kidney ischemia-reperfusion injury, HMGB1 preconditioning provided additional protection to TLR2 but not TLR4 knockout mice. The protective effect of rHMGB1 preconditioning involved Siglec-G upregulation, a negative regulator of HMGB1-mediated TLR4 pathway activation. Thus, preconditioning with rHMGB1 affords significant protection from TLR4-dependent kidney ischemia-reperfusion injury, indicating therapeutic potential.

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Section: Discussionsupporting

confidence: 92%

“…Protection from IRI by rHMGB1 preconditioning involves HMGB1-TLR4 interaction TLR2, TLR4, and RAGE are known endogenous receptors for HMGB1. RAGE has been shown not to be a mediator of kidney IRI, 17 whereas both TLR2 (see ref. 4) and TLR4 (see ref.…”

Section: Tubular Epithelial Cell Apoptosis Was Reduced In the Iri Kidmentioning

confidence: 99%

Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia–reperfusion injury in mice

Steenstra

Boer

et al. 2014

Kidney International

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“…Furthermore, infiltrated neutrophils and macrophages reduce renal blood flow, which leads to microcirculatory dysfunction [44,45]. Pro-inflammatory cytokines IL-1β, IL-6, TNF-α, and HMGB1 [46,47] are closely associated with renal IRI, a high level of which is considered a marker of severity of renal injury. The expression of these cytokines was significantly increased after IRI [48].…”

Section: Resultsmentioning

confidence: 99%

The Effect of Autophagy on Inflammation Cytokines in Renal Ischemia/Reperfusion Injury

et al. 2015

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Acute kidney injury (AKI) is characterized by a rapid loss of kidney function and an antigen-independent inflammatory process that causes tissue damage, which was one of the main manifestations of kidney ischemia/reperfusion (I/R). Recent studies have demonstrated autophagy participated in the pathological process of acute kidney injury. In this study, we discuss how autophagy regulated inflammation response in the kidney I/R. AKI was performed by renal I/R. Autophagy activator rapamycin (Rap) and inhibitor 3-methyladenine (MA) were used to investigate the role of autophagy on kidney function and inflammation response. After the experiment, kidney tissues were obtained for the detection of autophagy-related protein microtubule-associated protein light chain 3(LC3)II, Beclin1, and Rab7 and lysosome-associated membrane protein type (LAMP)2 protein by reverse transcription-polymerase chain reaction (PT-PCR) and Western blotting, and histopathology and tissue injury scores also. The blood was harvested to measure kidney function (creatinine (Cr) and blood urea nitrogen (BUN) levels) after I/R. Cytokines TNF-α, IL-6, HMGB1, and IL-10 were measured after I/R. I/R induced the expression of LC3II, Beclin1, LAMP2, and Rab7. The activation and inhibition of autophagy by rapamycin and 3-MA were promoted and attenuated histological and renal function in renal I/R rats, respectively. Cytokines TNF-α, IL-6, and HMGB1 were decreased, and IL-10 was further increased after activation of autophagy treated in I/R rats, while 3-MA exacerbated the pro-inflammatory cytokines TNF-α, IL-6, HMGB1, and anti-inflammatory cytokine IL-10 in renal I/R. I/R can activated the autophagy, and autophagy increase mitigated the renal injury by decreasing kidney injury score, levels of Cr and BUN after renal I/R, and inflammation response via regulating the balance of pro-inflammation and anti-inflammation cytokines.

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“…The infiltrated neutrophils and macrophages reduce blood flow in kidney, resulting dysfunction of the microcirculation ( 49 , 50 ). The levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α and HMGB1, have been reported to significantly increase following renal I/R injury in rats, which demonstrates that cytokines may be used as an indicator of severity of kidney damage ( 51 ). In the present study, rats in the renal I/R injury group demonstrated an increase in the levels of pro-inflammatory cytokines TNF-α, IL-6 and HMGB, and a reduction in the levels of the anti-inflammatory cytokine IL-10 at 24h post-renal I/R injury, when compared with the sham group.…”

Section: Discussionmentioning

confidence: 99%

Niclosamide attenuates inflammatory cytokines via the autophagy pathway leading to improved outcomes in renal ischemia/reperfusion injury

Zhang

Zhao

Sun

et al. 2017

Molecular Medicine Reports

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Renal ischemia/reperfusion (I/R) injury is a debilitating condition that leads to loss renal function and damage to kidney tissue in the majority of patients with acute kidney disease. Previous studies have indicated that autophagy serves a protective function in renal I/R injury. In the present study, the effect of the anthelmintic niclosamide in the regulation of inflammatory responses in kidney I/R was investigated. A total of 40 Sprague-Dawley rats were randomly divided into the following 5 groups (n=8 in each group): Sham group; renal I/R injury; renal I/R injury plus 3-methyladenine (3-MA) treatment (15 mg/kg); renal I/R injury plus niclosamide (25 mg/kg); and renal I/R injury plus rapamycin (10 mg/kg). The expression levels of autophagy-associated proteins in kidney samples obtained from rats with I/R injury were examined using reverse transcription-quantitative polymerase chain reaction and western blotting techniques. In addition, histopathological alterations, the expression of cytokines and renal function were evaluated. Treatment with niclosamide was associated with induction of autophagy and an overall improvement in renal function. There was an increased expression of autophagosome-associated proteins, suggesting a strong correlation between autophagy and improvement of renal function. The increased levels of anti-inflammatory cytokines and decreased levels of pro-inflammatory cytokines provided additional evidence that niclosamide may be effective for the treatment of renal I/R injury. Clinical studies are required to further validate the results of the present study.

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RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

Cited by 20 publications

References 68 publications

Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia–reperfusion injury in mice

Preconditioning with recombinant high-mobility group box 1 protein protects the kidney against ischemia–reperfusion injury in mice

The Effect of Autophagy on Inflammation Cytokines in Renal Ischemia/Reperfusion Injury

Niclosamide attenuates inflammatory cytokines via the autophagy pathway leading to improved outcomes in renal ischemia/reperfusion injury

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