Amelioration of acute kidney injury in lipopolysaccharide-induced systemic inflammatory response syndrome by an aldose reductase inhibitor, fidarestat

• Published in: PloS one 2012-01, Vol.7 (1), p.e30134
• Main Authors: Takahashi, Kazunori, Mizukami, Hiroki, Kamata, Kosuke, Inaba, Wataru, Kato, Noriaki, Hibi, Chihiro, Yagihashi, Soroku
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - blood; Acute Kidney Injury - complications; Acute Kidney Injury - drug therapy; Acute Kidney Injury - prevention & control; Aldehyde reductase; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - metabolism; Aldose reductase; Animals; Apoptosis; Apoptosis - drug effects; Biology; Blotting, Western; Creatinine; Cytokines; Cytokines - blood; Cytokines - genetics; Degeneration; Failure; Gene Expression Regulation - drug effects; Health aspects; Heart diseases; Heart failure; Imidazolidines - pharmacology; Imidazolidines - therapeutic use; Infiltration; Inflammation; Inflammatory response; Inhibitors; Injection; Injury prevention; Interleukin 6; Interleukins; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Kinases; Lethality; Leukocytes (neutrophilic); Lipopolysaccharides; Liver; Lungs; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Male; Medicine; Metabolites; Metastases; Mice; Mice, Inbred C57BL; Mitogens; Monocyte chemoattractant protein 1; Monosaccharides; Mortality; mRNA; Neutrophils - drug effects; Neutrophils - metabolism; Neutrophils - pathology; Organ Specificity - drug effects; Organ Specificity - genetics; Organs; Pathology; Polymers - metabolism; Polyols; Renal failure; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Sorbitol; Spleen; Survival Analysis; Systemic inflammatory response syndrome; Systemic Inflammatory Response Syndrome - complications; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - pathology; Time Factors; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Urea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030134

Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism. Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney. Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation. AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.