Acute hepatic ischemic-reperfusion injury induces a renal cortical "stress response," renal "cytoresistance," and an endotoxin hyperresponsive state

• Published in: American journal of physiology. Renal physiology 2014-10, Vol.307 (7), p.F856-F868
• Main Authors: Zager, Richard A, Johnson, Ali C M, Frostad, Kirsten B
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - pathology; Acute-Phase Proteins - metabolism; Animals; Cell Line; Chemokine CCL2 - metabolism; Endotoxemia - metabolism; Enzymes; Heme Oxygenase-1 - metabolism; Hemopexin - metabolism; Hepcidins - metabolism; Kidney - metabolism; Kidney - pathology; Kidney Cortex - metabolism; Kidney Cortex - pathology; Kidney Cortex - physiopathology; Kidney diseases; Lipocalin-2; Lipocalins - metabolism; Lipopolysaccharides; Liver Failure, Acute - complications; Liver Failure, Acute - pathology; Liver Failure, Acute - physiopathology; Male; Membrane Proteins - metabolism; Mice; Oncogene Proteins - metabolism; Protein expression; Reperfusion Injury - complications; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Rodents; Stress, Physiological; Toll-Like Receptor 4 - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00378.2014

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.