title: Acute hepatic ischemic-reperfusion injury induces a renal cortical "stress response," renal "cytoresistance," and an endotoxin hyperresponsive state.
abstract: Hepatic ischemic-reperfusion injury (HIRI) is considered a risk factor for clinical acute kidney injury (AKI). However, HIRI's impact on renal tubular cell homeostasis and subsequent injury responses remain ill-defined. To explore this issue, 30-45 min of partial HIRI was induced in CD-1 mice. Sham-operated or normal mice served as controls. Renal changes and superimposed injury responses (glycerol-induced AKI; endotoxemia) were assessed 2-18 h later. HIRI induced mild azotemia (blood urea nitrogen ∼45 mg/dl) in the absence of renal histologic injury or proteinuria, implying a "prerenal" state. However, marked renal cortical, and isolated proximal tubule, cytoprotective "stress protein" gene induction (neutrophil gelatinase-associated lipocalin, heme oxygenase-1, hemopexin, hepcidin), and increased Toll-like receptor 4 (TLR4) expression resulted (protein/mRNA levels). Ischemia caused release of hepatic heme-based proteins (e.g., cytochrome c) into the circulation. This corresponded with renal cortical oxidant stress (malondialdehyde increases). That hepatic derived factors can evoke redox-sensitive "stress protein" induction was implied by the following: peritoneal dialysate from HIRI mice, soluble hepatic extract, or exogenous cytochrome c each induced the above stress protein(s) either in vivo or in cultured tubule cells. Functional significance of HIRI-induced renal "preconditioning" was indicated by the following: 1) HIRI conferred virtually complete morphologic protection against glycerol-induced AKI (in the absence of hyperbilirubinemia) and 2) HIRI-induced TLR4 upregulation led to a renal endotoxin hyperresponsive state (excess TNF-α/MCP-1 gene induction). In conclusion, HIRI can evoke "renal preconditioning," likely due, in part, to hepatic release of pro-oxidant factors (e.g., cytochrome c) into the systemic circulation. The resulting renal changes can impact subsequent AKI susceptibility and TLR4 pathway-mediated stress.
authors: The Fred Hutchinson Cancer Research Center, Seattle, Washington; and University of Washington, Seattle, Washington dzager@fhcrc.org.
authors: Richard A
authors: RA
authors: Zager
authors: The Fred Hutchinson Cancer Research Center, Seattle, Washington; and University of Washington, Seattle, Washington.
authors: Ali C M
authors: AC
authors: Johnson
authors: The Fred Hutchinson Cancer Research Center, Seattle, Washington; and University of Washington, Seattle, Washington.
authors: Kirsten B
authors: KB
authors: Frostad
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology; D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D019446:Endotoxemia / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006466:Hemopexin / Q000378:metabolism; D064451:Hepcidins / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D008070:Lipopolysaccharides; D017114:Liver Failure, Acute / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D013312:Stress, Physiological; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D064451:Hepcidins; D000071068:Lipocalin-2; D054834:Lipocalins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D015513:Oncogene Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C071332:Lcn2 protein, mouse; D006466:Hemopexin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: acute kidney injury; hepatic ischemic-reperfusion injury; hepatic renal preconditioning