fr-167653 and Renal-Insufficiency

Acute tubular necrosis (ATN) secondary to induced warm ischemia (WI) results in inflammatory and delayed fibrotic processes and remains a common clinical problem with serious consequences. Because tumor necrosis factor-alpha (TNF-alpha) is a prominent proinflammatory factor implicated in the pathophysiology of acute renal ischemia reperfusion injury (IRI), we hypothesized that FR167653 (FR), a potent inhibitor of TNF-alpha and interleukin-1beta production, may reduce IRI.. IRI was induced in male pigs by bilateral clamping of the renal pedicle for 90 minutes (WI90), or unilateral renal clamping (90 minutes) after contralateral nephrectomy (1/2Nx90), or unilateral renal clamping without contralateral nephrectomy (WIuni90). FR was administered intravenously 60 minutes before WI (1 mg/kg/h), during WI, and continuously for 3 hours (1 mg/kg/h) during reperfusion in treated groups (FRWI90, FR1/2Nx90, or FRWIuni90). Blood and urine samples were collected between day 1 and 3 months after reperfusion for assessment of renal function. Kidneys were excised and renal tissues were collected at 3 months for morphologic and inflammation evaluation and protein analysis. Experimental groups were compared with sham operated (control) and heminephrectomized (Unif) groups without renal ischemia.. Three WI90 animals (43%) and five 1/2Nx90 (70%) were euthanized and necropsied at day 7 because of no urine production or poor conditions. Mortality was significantly improved after FR treatment. Survival was 100% in the control, Unif, WIuni90, and FR groups. In Unif groups, FR significantly reduced renal failure and bilateral renal ischemia (P < .05). At 3 months, proteinuria was significantly reduced in FR-treated groups (P < .01). Inflammatory cells count was also dramatically diminished in FR-treated pigs (P < .01 for CD3-positive cells). The second aspect of transient ischemia is the fibrotic process determined at 3 months. FR treatment was characterized by a reduction of renal fibrosis, particularly in Unif groups. TNF-alpha protein expression was diminished in FR-treated groups.. This is the first evidence that FR reduced the early and long-term effect of WI in the severe ischemia model. This effect was particularly marked against fibrosis and inflammation, which would contribute to deterioration of a patient's renal function.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Constriction; Disease Models, Animal; Fibrosis; Inflammation; Infusions, Intravenous; Interleukin-1; Kidney; Kidney Function Tests; Male; Necrosis; Nephrectomy; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proteinuria; Pyrazoles; Pyridines; Recovery of Function; Renal Insufficiency; Reperfusion Injury; Swine; Time Factors; Tumor Necrosis Factor-alpha; Warm Ischemia

Renal ischaemia is accompanied by acute and chronic complications. Tumour necrosis factor (TNF) alpha production via p38 mitogen-activated protein kinase (MAPK) is one of the pivotal mechanisms linking ischaemia to inflammation and could be a therapeutic target. FR167653 (FR), an inhibitor of p38 MAPK and TNF-alpha production, may ameliorate renal damage through its effects on TNF-alpha.. Warm ischaemia (WI) was induced in male pigs by bilateral clamping of the renal pedicle for 60 min or unilateral renal clamping after contralateral nephrectomy. FR was administered before and during WI, and continuously for 3 h during reperfusion in pigs exposed to the same WI conditions. Experimental groups were compared with sham-operated pigs and those subjected to unilateral nephrectomy without renal ischaemia. Renal function, fibrosis and inflammation were evaluated, and expression of monocyte chemoattractant protein 1, transforming growth factor beta and TNF-alpha was determined after 12 weeks.. FR significantly reduced renal failure in groups subjected to unilateral nephrectomy and bilateral renal ischaemia. Proteinuria was significantly reduced, and inflammation and expression of proinjury proteins were diminished, accompanied by a reduction in renal fibrosis.. Control of TNF-alpha production and activity prevents renal damage after prolonged WI.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Immunohistochemistry; Kidney; Male; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Renal Insufficiency; Reperfusion Injury; Swine; Tumor Necrosis Factor-alpha; Warm Ischemia

The p38 mitogen-activated protein kinase (MAPK) pathway is a proinflammatory signal transduction pathway for the production of cytokines and cellular response to stress, such as bacterial LPS or ischemia. We examined the effects of FR167653, a specific inhibitor of p38 MAPK, to explore the relationship between intestinal barrier damage and remote renal dysfunction. Immunohistochemical data showed the accumulation of neutrophils in the intestine after burn, and a horseradish peroxidase (HRP) tracer experiment showed burn-induced intestinal barrier damage. Our quantitative bacterial culture data demonstrated that viable bacteria reached the remote organs after burn and prevented the invading viable bacteria from using FR167653. Western blotting identified increased phosphorylation of p38 MAPK in the kidney after burn, and it may also have shown the possibility that endotoxin associated with the bacterial translocation enhances the activation of the p38 MAPK pathway. We blocked the intestinal barrier damage using FR167653, which resulted in reduced neutrophils in the intestine. FR167653 also prevented the increased phosphorylation of p38 MAPK in the kidney, which resulted in reduced neutrophils in the glomerulus and the reduction of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta mRNA in the kidneys, and, finally, prevented burn-induced renal failure. This study provides evidence for the hypothesis that the p38 MAPK pathway controls inflammatory mediators and not only improves intestinal function but also reduces remote renal failure after burn. We identified the pathophysiologic role of the p38 MAPK pathway in the development of renal failure after burn.

Topics: Animals; Animals, Newborn; Bacterial Translocation; Burns; Enzyme Inhibitors; Interleukin-1; Intestines; Jejunum; Kidney; Male; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Pyrazoles; Pyridines; Rats; Rats, Wistar; Renal Insufficiency; Tumor Necrosis Factor-alpha