TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity

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 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.

Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice

“…TLR4 signalling also plays an important role in the development of various kidney diseases, yet the role of TLR4 in diabetic glomerulopathy or hyperlipidaemiainduced kidney damage remains to be elucidated [8][9][10][11][12][13]. Recently, Burkhardt et al and Bouma et al reported that serum S100A8/A9 complex concentrations were elevated in patients with diabetes [33,34].…”

“…TLR4, one of the best-characterised TLRs, binds with lipopolysaccharide from Gram-negative bacterial cell walls and with several endogenous ligands [7]. TLR4 also plays an important role in various kidney disorders, such as glomerulonephritis, renal ischaemia and diabetic tubular inflammation [8][9][10][11][12][13], but the role of TLR4 in diabetic glomerular injury and hyperlipidaemia-induced kidney damage remains largely unknown.…”

Sepsis and Acute Kidney Injury

“…TLR-4 appears to play a key inflammatory role in AKI. 29 There is a significant up-regulation of monocytic TLR-2 and TLR-4 expression in septic patients when compared with healthy individuals. 30,31 In addition, the expression of TLR-2 and TLR-4 in hepatic and splenic macrophages is significantly increased in mice with experimental peritonitis induced by cecal ligation and puncture.…”

The Inflammasomes in Kidney Disease

“…This arm of the immune system involves several distinct families of soluble and cellular receptors that activate proinflammatory signaling pathways ( Figure 1). These cellular receptors include Toll-like receptors (TLRs), [1][2][3][4] retinoic acid-induced gene-like receptors, nucleotide-binding domain-leucine-rich repeat (or NOD-like receptors; NLRs), scavenger receptors, and C-type lectins that are activated by various bacterial and viral pathogen-associated molecular patterns (PAMPs), resulting the engagement of nuclear factor-B (NF-B), 5 IFN regulatory factors, and mitogen-activated protein kinase signaling pathways modulating proinflammatory and type I IFN genes.…”