Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects

• Published in: Kidney international Vol. 69; no. 9; pp. 1535 - 1542
• Main Authors: Yasuda, H., Yuen, P.S.T., Hu, X., Zhou, H., Star, R.A.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-05-2006; Nature Publishing; Elsevier Limited
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - etiology; Animals; Antibodies - pharmacology; Bacterial diseases; Bacterial sepsis; Biological and medical sciences; Blood Vessels - drug effects; Delayed-Action Preparations - administration & dosage; extravasation; Human bacterial diseases; hypoxia; Hypoxia - drug therapy; Infectious diseases; inflammation; Kidney Tubules - blood supply; Kidney Tubules - drug effects; Kidney Tubules - pathology; Kidneys; Lipids - blood; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microcirculation - drug effects; microvascular permeability; Nephrology. Urinary tract diseases; Permeability; Renal Circulation - drug effects; Sepsis - complications; Sepsis - drug therapy; Sepsis - metabolism; Simvastatin - administration & dosage; TNF-α; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism; Urinary system involvement in other diseases. Miscellaneous; hypoxia; extravasation; TNF-α; microvascular permeability; inflammation; Nephrology; Epidemiology; Urology; Sepsis syndrome; Microcirculation; Extravasation; Blood vessel; Tumor necrosis factor α; Kidney disease; Oxygen; Urinary system disease; Enzyme; Mortality; Simvastatin; Acute kidney injury; Cytokine; Enzyme inhibitor; Statin derivative; Inflammation; Permeability; Bacteremia; Infection; Bacteriosis; Hydroxymethylglutaryl-CoA reductase; Hypoxia; Circulatory system; Oxidoreductases; Antilipemic agent
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/sj.ki.5000300

Acute kidney injury (AKI) occurs in about half of patients in septic shock and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently required. Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors that also have pleiotropic actions. They have been reported to increase the survival of septic or infectious patients. But the effect of simvastatin, a widely used statin, on sepsis-induced AKI is unknown. The effects of simvastatin and tumor necrosis factor (TNF)-α neutralizing antibody were studied in a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice. Simvastatin significantly improved CLP-induced mortality and AKI. Simvastatin attenuated CLP-induced tubular damage and reversed CLP-induced reduction of intrarenal microvascular perfusion and renal tubular hypoxia at 24 h. Simvastatin also restored towards normal CLP-induced renal vascular protein leak and serum TNF-α. Neither delayed simvastatin therapy nor TNF-α neutralizing antibody improved CLP-induced AKI. Simvastatin improved sepsis-induced AKI by direct effects on the renal vasculature, reversal of tubular hypoxia, and had a systemic anti-inflammatory effect.