Cytokines induce small intestine and liver injury after renal ischemia or nephrectomy.
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 showed 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 with 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 because of 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.
Park
Sang Won
SW
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032-3784, USA.
Chen
Sean W C
SW
Kim
Mihwa
M
Brown
Kevin M
KM
Kolls
Jay K
JK
D'Agati
Vivette D
VD
Lee
H Thomas
HT
D000208:Acute Disease; D058186:Acute Kidney Injury / Q000150:complications*; D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D016207:Cytokines / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D020381:Interleukin-17 / Q000097:blood / Q000172:deficiency / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000172:deficiency / Q000235:genetics; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy / Q000009:adverse effects*; D053722:Receptors, Interleukin-17 / Q000172:deficiency / Q000235:genetics; D015427:Reperfusion Injury / Q000150:complications; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000172:deficiency / Q000235:genetics
D016207:Cytokines; D020381:Interleukin-17; D015850:Interleukin-6; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha