title: Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging.
abstract: Urine output is widely used as a criterion for the diagnosis of AKI. Although several potential mechanisms of septic AKI have been identified, regulation of urine flow after glomerular filtration has not been evaluated. This study evaluated changes in urine flow in mice with septic AKI. The intratubular urine flow rate was monitored in real time by intravital imaging using two-photon laser microscopy. The tubular flow rate, as measured by freely filtered dye (FITC-inulin or Lucifer yellow), time-dependently declined after LPS injection. At 2 hours, the tubular flow rate was slower in mice injected with LPS than in mice injected with saline, whereas BP and GFR were similar in the two groups. Importantly, fluorophore-conjugated LPS selectively accumulated in the proximal tubules that showed reduced tubular flow at 2 hours and luminal obstruction with cell swelling at 24 hours. Delipidation of LPS or deletion of Toll-like receptor 4 in mice abolished these effects, whereas neutralization of TNF-α had little effect on LPS-induced tubular flow retention. Rapid intravenous fluid resuscitation within 6 hours improved the tubular flow rate only when accompanied by the dilation of obstructed proximal tubules with accumulated LPS. These findings suggest that LPS reduces the intratubular urine flow rate during early phases of endotoxemia through a Toll-like receptor 4-dependent mechanism, and that the efficacy of fluid resuscitation may depend on the response of tubules with LPS accumulation.
authors: Departments of Pharmacology and dnakano@med.kagawa-u.ac.jp.
authors: Daisuke
authors: D
authors: Nakano
authors: Department of Emergency and Critical Care Medicine, University Hospital, University of Tokyo, Tokyo; and.
authors: Kent
authors: K
authors: Doi
authors: Anesthesiology, Kagawa University, Kagawa;
authors: Hiroaki
authors: H
authors: Kitamura
authors: Department of Nephrology and.
authors: Takashige
authors: T
authors: Kuwabara
authors: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Kiyoshi
authors: K
authors: Mori
authors: Department of Nephrology and.
authors: Masashi
authors: M
authors: Mukoyama
authors: Departments of Pharmacology and.
authors: Akira
authors: A
authors: Nishiyama
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001794:Blood Pressure; D019446:Endotoxemia / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D005440:Fluid Therapy; D005919:Glomerular Filtration Rate; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009846:Oliguria / Q000150:complications / Q000503:physiopathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D014563:Urodynamics / Q000187:drug effects
chemical_list: D000906:Antibodies; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
keywords: ARF; LPS; oliguria; renal tubular epithelial cells