TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity
Open Access
- 1 May 2008
- journal article
- Published by Wolters Kluwer Health in Journal of the American Society of Nephrology
- Vol. 19 (5), 923-932
- https://doi.org/10.1681/asn.2007090982
Abstract
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 wild-type mice had significantly more renal dysfunction, histologic damage, and leukocytes infiltrating the kidney than similarly treated mice with a targeted deletion of TLR4 [Tlr4(−/−)]. 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(−/−) mice. Activation of JNK and p38, which was associated with cisplatin-induced renal injury in wild-type mice, was significantly blunted in Tlr4(−/−) 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-α and subsequent kidney injury. Targeting the TLR4 signaling pathways may be a feasible therapeutic strategy to prevent cisplatin-induced AKI in humans.Keywords
This publication has 62 references indexed in Scilit:
- TLR4 activation mediates kidney ischemia/reperfusion injuryJCI Insight, 2007
- Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in miceAmerican Journal of Physiology-Renal Physiology, 2007
- Toll-like receptor (TLR4) shedding and depletion: acute proximal tubular cell responses to hypoxic and toxic injuryAmerican Journal of Physiology-Renal Physiology, 2007
- Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: Acute renal failure is dependent on MyD88 but not renal cell apoptosisKidney International, 2006
- Role of CXC Chemokine Receptor 3 Pathway in Renal Ischemic InjuryJournal of the American Society of Nephrology, 2006
- Cisplatin Increases TNF-α mRNA Stability in Kidney Proximal Tubule CellsRenal Failure, 2006
- Ischemic acute renal failure: An inflammatory disease?Kidney International, 2004
- Reduced Myocardial Ischemia-Reperfusion Injury in Toll-Like Receptor 4-Deficient MiceCirculation, 2004
- The Endoplasmic Reticulum-resident Heat Shock Protein Gp96 Activates Dendritic Cells via the Toll-like Receptor 2/4 PathwayJournal of Biological Chemistry, 2002
- Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling PathwaysScience, 1997