title: Atorvastatin improving renal ischemia reperfusion injury via direct inhibition of active caspase-3 in rats.
abstract: Caspase-3 is a key molecule involved in the inflammation and apoptosis of ischemia reperfusion (IR) injury. Statins are known to inhibit IR injury, but the mechanism of action remains uncertain. In the present study, the effect and underlying mechanism of ischemia alone, and reperfusion with or without atorvastatin (AT) as a timed intervention were examined, since clinically the kidney is only exposed to drug delivery during reperfusion. Male Sprague-Dawley rats were subjected to 45-min clamping of the left renal hilus followed by four hours reperfusion with a right nephrectomy. AT 10 mg/kg was intravenously administered after clamping the renal hilus, but prior to kidney reperfusion. Ischemia alone did cause tubulointerstitial damage (TID), protein carbonylation and caspase-3 activation with an increase in 12 kDa subunit, while reperfusion further enhanced TID, monocyte (ED-1+ cell) infiltration, apoptosis and necrosis together with caspase-3 activity and 17 kDa subunit, but reversed protein carbonylation. AT significantly reduced TID (26%), ED-1+ cell infiltration (74%), tubular apoptosis (47%) and necrosis (73%), and interstitial apoptosis (64%), as well as caspase-3 activity (26%), but did not change serum creatinine and cholesterol. Importantly, without affecting either caspase-3 active protein cleavage or S-nitrosylation, AT directly inhibited caspase-3 active enzyme in a dose-dependent manner in vitro. In conclusions, IR and AT exerted opposing effects on caspase-3 activity by differing mechanisms, with IR stimulating caspase-3 proteolytic cleavage and AT inhibiting active caspase-3 enzyme. This new inhibitory mechanism of AT may improve reperfusion tolerance in ischemic kidneys and benefit transplant recipients.
authors.affiliation: Academic Nephrology Unit, University of Sheffield, Sheffield, UK.
authors.forename: John L
authors.initials: JL
authors.lastname: Haylor
authors.forename: Kevin P G
authors.initials: KP
authors.lastname: Harris
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nicholson
authors.forename: Helen L
authors.initials: HL
authors.lastname: Waller
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis; D000069059:Atorvastatin; D061945:Caspase Inhibitors; D003404:Creatinine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006538:Heptanoic Acids / Q000008:administration & dosage*; D007684:Kidney Tubules / Q000473:pathology; D008657:Metabolic Clearance Rate; D020011:Protective Agents / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D020011:Protective Agents; D011758:Pyrroles; D000069059:Atorvastatin; D003404:Creatinine