Pravastatin, A 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Renal Injury in an Experimental Model of Ischemia-Reperfusion

Joyce, Michael; Kelly, C. J.; Winter, D. C.; Chen, Gang; Leahy, A.; Bouchier‐Hayes, David

doi:10.1006/jsre.2001.6256

Cited by 76 publications

(61 citation statements)

References 38 publications

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“…12,19,27,36 These kinds of drugs have been described as prophylactic agents to treat I/R injuries. 37 Moreover, we recently suggested that simvastatin could be used as a supplement for organ preservation solutions due to its capability to sustain the expression of KLF2-derived vasoprotective transcriptional pathways in cold-stored endothelial cells. 11 Here we demonstrate that the addition of simvastatin to UWS, a commonly used cold-storage solution, maintains KLF2-derived vasoprotective pathways during short and long periods of cold liver ischemia.…”

Section: Discussionmentioning

confidence: 99%

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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Pathophysiological alterations in the endothelial phenotype result in endothelial dysfunction. Flow cessation, occurring during organ procurement for transplantation, triggers the endothelial dysfunction characteristic of ischemia/reperfusion injury, partly due to a reduction in the expression of the vasoprotective transcription factor Kruppel-like Factor 2 (KLF2). We aimed at (1) characterizing the effects of flow cessation and cold storage on hepatic endothelial phenotype, and (2) ascertaining if the consequences of cold stasis on the hepatic endothelium can be pharmacologically modulated, improving liver graft function. Expression of KLF2 and its vasoprotective programs was determined in (i) hepatic endothelial cells (HEC) incubated under cold storage conditions with or without the KLF2-inducer simvastatin, and (ii) rat livers not cold stored or preserved in cold University of Wisconsin solution (UWS) supplemented with simvastatin or its vehicle. In addition, upon warm reperfusion hepatic vascular resistance, endothelial function, nitric oxide vasodilator pathway, apoptosis, inflammation, and liver injury were evaluated in not cold stored livers or livers preserved in cold UWS supplemented with simvastatin or vehicle. Expression of KLF2 and its vasoprotective programs decrease in HEC incubated under cold storage conditions. Cold-stored rat livers exhibit a time-dependent decrease in KLF2 and its target genes, liver injury, increased hepatic vascular resistance, and endothelial dysfunction. The addition of simvastatin to the storage solution, maintained KLF2-dependent vasoprotective programs, prevented liver damage, inflammation, and oxidative stress and improved endothelial dysfunction. Conclusion: Our results provide a rationale to evaluate the beneficial effects of a vasoprotective preservation solution on human liver procurement for transplantation. (HEPATOLOGY 2012;55:921-930)

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Section: Discussionmentioning

confidence: 99%

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

et al. 2012

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“…Skeletal muscle injury, measured by edema, leucosequestration and electrical properties, were significantly lower with pravastatin pretreatment than in the untreated group. Although previous work has demonstrated the anti-inflammatory properties of pravastatin in renal and cardiac models of ischemia reperfusion injury, its effect on skeletal muscle ischemia reperfusion has not been studied previously (Lefer et al 1999, Joyce et al 2001.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelium-derived NO is a potent vasodilator that regulates mean arterial blood pressure, and it has also been shown to reduce leukocyte and platelet activation and aggregation (Kubes et al 1991, Gaboury et al 1993. Previous work has demonstrated that pretreatment with HMG CoA reductase inhibitors can reduce the extent of cerebral infarction and also attenuate renal injury in an experimental model of ischemia reperfusion injury by the upregulation of constitutive endothelial nitric oxide synthase (ecNOS) (Endres et al 1998, Joyce et al 2001. However, the involvement of nitric oxide in skeletal muscle ischemia reperfusion injury remains controversial, and has been shown to be both beneficial and deleterious in this setting.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is believed that statins have anti-inflammatory properties independent of their cholesterol-lowering properties, and have indeed been shown to attenuate renal and cardiac injury in a number of models of ischemia reperfusion (Lefer et al 1999, Joyce et al 2001. Furthermore, statins have been shown to inhibit the generation of superoxide in activated neutrophils by reducing tyrosine phosphorylation, and to reduce endotoxin-induced leukocyte endothelial cell interactions (Kanno et al 1999, Pruefer et al 2002.…”

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Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

et al. 2006

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Background Revascularization of a limb following prolonged ischemia results in substantial skeletal muscle injury. Statins play a well-understood role in the treatment of hypercholesterolemia but are also known to have anti-inflammatory properties. The purpose of this study was to examine the effects of pravastatin pre-treatment in the setting of skeletal muscle ischemia reperfusion injury (IRI).Methods Adult male Sprague Dawley rats (n = 27) were randomized into 3 groups: control group, I/R group, IR group pre-treated with pravastatin. Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanters for 2.5 h. Treatment groups received normal saline in equal volumes prior to tourniquet release. Following 12 h reperfusion, the tibialis anterior muscle was dissected and muscle function assessed electrophysiologically by electrical field stimulation. The animals were then killed and skeletal muscle harvested for evaluation.Results We found that pre-treatment with pravastatin reduces the tissue oxidative damage and edema associated with skeletal muscle reperfusion injury. Skeletal muscle injury, measured by edema, leucosequestration and electrical properties were significantly lower with pravastatin pre-treatment compared to the non-treated group.Interpretation We feel that pravastatin pre-treatment may be a potential therapeutic intervention for skeletal muscle ischemia reperfusion injury in the clinical setting.

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“…Recent studies in experimental models of chronic renal insufficiency demonstrate the efficacy of statins to ameliorate progressive nephropathy (5)(6)(7)(8)(9). Statins enhance renal blood flow (RBF) (5,10) and GFR (11) and attenuate vascular inflammation through vascular and glomerular nitric oxide production, as reviewed by McFarlane et al (12).…”

Section: Introductionmentioning

confidence: 99%

Effect of Pravastatin on Total Kidney Volume, Left Ventricular Mass Index, and Microalbuminuria in Pediatric Autosomal Dominant Polycystic Kidney Disease

Cadnapaphornchai

George

McFann

et al. 2014

Clinical Journal of the American Society of Nephrology

150

101

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Background and objectives In autosomal dominant polycystic kidney disease (ADPKD), progressive kidney cyst formation commonly leads to ESRD. Because important manifestations of ADPKD may be evident in childhood, early intervention may have the largest effect on long-term outcome. Statins are known to slow progressive nephropathy in animal models of ADPKD. This randomized double-blind placebo-controlled phase III clinical trial was conducted from 2007 to 2012 to assess the effect of pravastatin on height-corrected total kidney volume (HtTKV) and left ventricular mass index (LVMI) by magnetic resonance imaging (MRI) and urine microalbumin excretion (UAE) in children and young adults with ADPKD.Designs, setting, participants, & measurements There were 110 pediatric participants with ADPKD and normal kidney function receiving lisinopril who were randomized to treatment with pravastatin or placebo for a 3-year period with evaluation at 0, 18, and 36 months. The primary outcome variable was a $20% change in HtTKV, LVMI, or UAE over the study period.Results Ninety-one participants completed the 3-year study (83%). Fewer participants receiving pravastatin achieved the primary endpoint compared with participants receiving placebo (69% versus 88%; P=0.03). This was due primarily to a lower proportion reaching the increase in HtTKV (46% versus 68%; P=0.03), with similar findings observed between study groups for LVMI (25% versus 38%; P=0.18) and UAE (47% versus 39%; P=0.50). The percent change in HtTKV adjusted for age, sex, and hypertension status over the 3-year period was significantly decreased with pravastatin (23%63% versus 31%63%; P=0.02).Conclusions Pravastatin is an effective agent to slow progression of structural kidney disease in children and young adults with ADPKD. These findings support a role for early intervention with pravastatin in this condition.

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Pravastatin, A 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor, Attenuates Renal Injury in an Experimental Model of Ischemia-Reperfusion

Cited by 76 publications

References 38 publications

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

Addition of simvastatin to cold storage solution prevents endothelial dysfunction in explanted rat livers

Pravastatin attenuates tourniquet-induced skeletal muscle ischemia reperfusion injury

Effect of Pravastatin on Total Kidney Volume, Left Ventricular Mass Index, and Microalbuminuria in Pediatric Autosomal Dominant Polycystic Kidney Disease

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