Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy

Abstract

Patients with acute kidney injury (AKI) frequently suffer from extra-renal complications including hepatic dysfunction and systemic inflammation. We aimed to determine the mechanisms of AKI induced hepatic dysfunction and systemic inflammation. Mice subjected to AKI [renal ischemia reperfusion (IR) or nephrectomy] rapidly developed acute hepatic dysfunction and suffered significantly worse hepatic IR injury. After AKI, rapid peri-portal hepatocyte necrosis, vacuolization, neutrophil infiltration and pro-inflammatory mRNA upregulation were observed suggesting an intestinal source of hepatic injury. Small intestine histology after AKI demonstrated profound villous lacteal capillary endothelial apoptosis, disruption of vascular permeability and epithelial necrosis. After ischemic or non-ischemic AKI, plasma TNF-α, IL-17A and IL-6 increased significantly. Small intestine appears to be the source of IL-17A as IL-17A levels were higher in the portal circulation and small intestine compared to the levels measured from the systemic circulation and liver. Wild type mice treated with neutralizing antibodies against TNF-α, IL-17A or IL-6 or mice deficient in TNF-α, IL-17A, IL-17A receptor or IL-6 were protected against hepatic and small intestine injury due to ischemic or non-ischemic AKI. For the first time, we implicate the increased release of IL-17A from small intestine together with induction of TNF-α and IL-6 as a cause of small intestine and liver injury after ischemic or non-ischemic AKI. Modulation of the inflammatory response and cytokine release in the small intestine after AKI may have important therapeutic implications in reducing complications arising from AKI.

Possible Protective Effect of Bone Marrow-Mesenchymal Stem Cells (BM-MSCs) Against the Remote Liver Injury Induced by Renal Ischemia Reperfusion in Male Albino Rats

“…Renal IRI rapidly caused marked hepatic vacuolization evident sinusoidal dilatation, and vascular congestion. These results were supported by other researchers [1,7] who stated that liver cell injury and hepatocyte death (necrotic and apoptotic) occurred following renal IRI as a result of oxidative stress and decreased its antioxidant capacity. In addition, some investigators attributed liver cell damage to the microvascular reorganization of hepatic parenchyma [33].…”

“…The significant increase in serum urea and creatinine confirmed the occurrence of renal dysfunction and the altered serum AST and ALT indicated remote liver injury. Renal IRI induces an inflammatory response, which results in the formation of reactive oxygen species (ROS) that augments local tissue damage or affects organs remote from the site of IRI [1,5,6,9]. Several previous studies [16][17][18].…”

“…The increasing mortality rate in cases with acute renal injury necessitates designing strategies to assess the effect of renal injury on distant organs [11]. Therefore, several studies [8,[1][2][3][4][5][6][7][8][9][10][11][12][13][14] tried to protect liver from remote injury induced by renal IRI for the prevention and attenuation of acute renal injury related morbidity.…”

Effects of melatonin on the serum levels of pro-inflammatory cytokines and tissue injury after renal ischemia reperfusion in rats

“…22 It is shown that cytokines may have a role in small intestine and liver injury after renal ischemia. 34 Bilateral kidney IR injury leads to an increase in both systemic and cardiac TNF-a. 35 A recent study identified that ischemic AKI induces lung endothelial apoptosis via TNFR1 and limited data suggest a role for systemic elevation of inflammatory cytokines and apoptosis; however, the mechanism was not expressed clearly.…”

Robotic repair of a bilateral renal collecting system duplication: a case report and brief review of renal embryology

“…There is accumulating evidence that ischemia activates the immune system, and that this activation is both local and systemic, and involves the release of toxic cytokines, including TNF. 10,11 Additionally, this release of TNF may activate protective mechanisms in the form of superoxide dismutase. 12 This unique case provides the opportunity to discuss the organogenesis of the renal system.…”