Role of Toll-Like Receptor 4 in Endotoxin-Induced Acute Renal Failure

Abstract

Toll-like receptor 4 (TLR4) is present on monocytes and other cell types, and mediates inflammatory events such as the release of TNF after exposure to LPS. C3H/HeJ mice are resistant to LPS-induced mortality, due to a naturally occurring mutation in TLR4. We therefore hypothesized that LPS-induced acute renal failure (ARF) requires systemic TNF release triggered by LPS acting on extrarenal TLR4. We injected C3H/HeJ mice and C3H/HeOuJ controls with 0.25 mg of LPS, and sacrificed them 6 h later for analysis of blood urea nitrogen (BUN) and kidney tissue (n = 8 per group). In contrast to C3H/HeOuJ controls, C3H/HeJ mice were completely resistant to LPS-induced ARF (6-h BUN of 32.3 ± 1.1 vs 61.7 ± 5.6 mg/dl). C3H/HeJ mice released no TNF into the circulation at 2 h (0.00 vs 1.24 ± 0.16 ng/ml), had less renal neutrophil infiltration (6.4 ± 1.0 vs 11.4 ± 1.3 neutrophils per high power field), and less renal apoptosis, as assessed by DNA laddering. Transplant studies showed that C3H/HeJ recipients of wild-type kidneys (n = 9) were protected from LPS-induced ARF, while wild-type recipients of C3H/HeJ kidneys (n = 11) developed severe LPS-induced ARF (24-h BUN 44.0 ± 4.1 vs 112.1 ± 20.0 mg/dl). These experiments support our hypothesis that LPS acts on extrarenal TLR4, thereby leading to systemic TNF release and subsequent ARF. Renal neutrophil infiltration and renal cell apoptosis are potential mechanisms by which endotoxemia leads to functional ARF.

T Cells Modulate Neutrophil-Dependent Acute Renal Failure during Endotoxemia

“…PMN and their infiltration into the kidney have been proposed to cause renal dysfunction during sepsis (31)(32)(33). Our data provide additional experimental evidence for this concept of PMN-dependent organ failure during endotoxemia.…”

Upregulation of TLR4 mRNA Expression Levels in Broiler Chickens Under Acute Heat Stress

“…In addition, previous research has shown a marked increase in TLR2 and TLR4 expression in renal tubular cells and in renal infiltrating cells caused by ischemia and reperfusion injury compared with control group (Kim et al, 2005;Pedregosa et al, 2011). Cunningham et al (2004) reported that TLR4 expression in the kidneys was critical in mediating LPS-induced acute kidney failure via proinflammatory cytokine release and subsequent kidney damage. Those results indicate that TLR4 mRNA expression levels in the kidneys may be caused by renal tubular cells or renal infiltrating cells damage, or LPS induction under AHS.…”

TLR4 Signaling Mediates Inflammation and Tissue Injury in Nephrotoxicity

“…In contrast, the role of TLR4 in infection-related acute renal failure has not been firmly established. Although endotoxin-induced acute renal failure was shown to be completely dependent upon extrarenal TLR4, 16 acute renal failure in the cecal ligation and puncture model of polymicrobial sepsis was independent of TLR4 signaling. 44 Second, it is clear from the present studies that TLR4 is pivotal in initiating the intrarenal inflammatory response that occurs in cisplatin nephrotoxicity.…”

“…[11][12][13] The most extensively characterized Toll-like receptor, TLR4, is the receptor for the endotoxin of gram-negative bacteria. 14,15 Previous studies by Cunningham et al 16 demonstrated that endotoxininduced acute renal failure is completely dependent on TLR4 signaling. Likewise, we recently demon-strated that cisplatin and endotoxin exert synergistic renal toxicity that is TLR4-dependent.…”