The Role of Toll-Like Receptor 4 in Cisplatin-Induced Renal Injury

Cenedeze, Marcos Antônio; Gonçalves, Giselle Martins; Feitoza, Carla Q.; Wang, P.M.H.; Damião, Marcio José; Bertocchi, Ana Paula Fernandes; Pacheco-Silva, Álvaro; Câmara, Niels Olsen Saraiva

doi:10.1016/j.transproceed.2007.01.032

Cited by 26 publications

(21 citation statements)

References 6 publications

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“…Cenedeze et al 42 recently also reported resistance to cisplatin nephrotoxicity in mice having a point mutation in the TLR4 receptor. In addition, our findings (Supplemental data) and a recent report that appeared while this manuscript was under review 43 also demonstrate a similar role for TLR4 signaling in the pathogenesis of ischemic acute renal failure.…”

Section: Discussionmentioning

confidence: 92%

TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity

Zhang

Ramesh

Uematsu

et al. 2008

Journal of the American Society of Nephrology

281

256

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The molecular mechanisms of acute kidney injury (AKI) remain unclear. Toll-like receptors (TLRs), widely expressed on leukocytes and kidney epithelial cells, regulate innate and adaptive immune responses. The present study examined the role of TLR signaling in cisplatin-induced AKI. Cisplatin-treated wildtype mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(Ϫ/Ϫ)]. Levels of cytokines in serum, kidney, and urine were increased significantly in cisplatin-treated wild-type mice compared with saline-treated wild-type mice and cisplatin-treated Tlr4(Ϫ/Ϫ) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(Ϫ/Ϫ) mice. Using bone marrow chimeric mice, it was determined that renal parenchymal TLR4, rather than myeloid TLR4, mediated the nephrotoxic effects of cisplatin. Therefore, activation of TLR4 on renal parenchymal cells may activate p38 MAPK pathways, leading to increased production of inflammatory cytokines, such as TNF-␣ and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.

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Section: Discussionmentioning

confidence: 92%

TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity

Zhang

Ramesh

Uematsu

et al. 2008

Journal of the American Society of Nephrology

281

256

View full text Add to dashboard Cite

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“…Cisplatin increased the expression of TLR4 mRNA and protein in HEI-OC1 auditory cells Cenedeze et al (24) demonstrated that cisplatin-induced renal toxicity is significantly alleviated in C3H/HeJ mice producing a mutant form of TLR4 compared with that in C3H/HePas control mice. Furthermore, Tarang et al (10) reported that cisplatin induced the expression of TLRs in peritoneal macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…TLR4, as a pattern recognition receptor, is known to recognize its specific ligand LPS in innate immunity. By using TLR4 mutant C3H/HeJ mice, Cenedeze et al (24) reported that cisplatin-induced renal toxicity is partly mediated through TLR4. Ramesh et al (25) also demonstrated that the combination of cisplatin and LPS acts synergistically to produce inflammatory cytokines, such as TNF-a, IL-6, MCP-1, KC, and GM-CSF, thereby inducing nephrotoxicity in an acute renal failure model.…”

Section: Figurementioning

confidence: 99%

“…Although TLR-mediated signaling pathways play a critical role in the innate immune response (19), they are also involved in a variety of deleterious inflammatory diseases, such as autoimmune disease (20), rheumatoid arthritis (21), and Alzheimer's disease (22). It has been reported that in a mouse model of acute kidney injury, TLR4 signaling mediates cisplatin-induced production of proinflammatory cytokines, such as TNF-a, IL-6, and IL-1b, resulting in subsequent renal injury (23,24). In contrast, Ramesh et al (25,26) demonstrated that the combination of cisplatin and LPS, a typical PAMP in bacteria, synergistically induces renal dysfunction through the production of proinflammatory cytokines, including TNF-a, IL-6, and MCP-1: moreover, this renal dysfunction is completely dependent on TLR4 signaling.…”

mentioning

confidence: 99%

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Activation of Lipopolysaccharide–TLR4 Signaling Accelerates the Ototoxic Potential of Cisplatin in Mice

Kim

Choi

et al. 2011

The Journal of Immunology

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Dysfunction in immune surveillance during anticancer chemotherapy of patients often causes weakness of the host defense system and a subsequent increase in microbial infections. However, the deterioration of organ-specific function related to microbial challenges in cisplatin-treated patients has not yet been elucidated. In this study, we investigated cisplatin-induced TLR4 expression and its binding to LPS in mouse cochlear tissues and the effect of this interaction on hearing function. Cisplatin increased the transcriptional and translational expression of TLR4 in the cochlear tissues, organ of Corti explants, and HEI-OC1 cells. Furthermore, cisplatin increased the interaction between TLR4 and its microbial ligand LPS, thereby upregulating the production of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, via NF-κB activation. In C57BL/6 mice, the combined injection of cisplatin and LPS caused severe hearing impairment compared with that in the control, cisplatin-alone, or LPS-alone groups, whereas this hearing dysfunction was completely suppressed in both TLR4 mutant and knockout mice. These results suggest that hearing function can be easily damaged by increased TLR expression and microbial infections due to the weakened host defense systems of cancer patients receiving therapy comprising three to six cycles of cisplatin alone or cisplatin combined with other chemotherapeutic agents. Moreover, such damage can occur even though patients may not experience ototoxic levels of cumulative cisplatin concentration.

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“…However, several studies using whole blood assays have not shown any correlation between TLR-4 polymorphism and lower expression of cytokines [14,15]. In a study with TLR-4 deficient animals, it was shown that these animals presented less renal dysfunction after cisplatin administration with lower production of TNF-α [16]. In another study, the early mRNA TNF-α renal expression after ischemia and reperfusion injury was found to be partly responsible for the renal dysfunction [17], possibly being secreted after stimulation of innate immunity.…”

Section: Discussionmentioning

confidence: 98%