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

doi:10.1006/jsre.2001.6256

Journal of Surgical Research

Volume 101, Issue 1, November 2001, Pages 79-84

https://doi.org/10.1006/jsre.2001.6256 Get rights and content

Abstract

Background. Renal dysfunction due to ischemia-reperfusion (IR) injury is a common problem following renovascular surgery or kidney transplantation. There is a lot of emerging evidence that statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have anti-inflammatory properties and exert direct beneficial effects on the vascular endothelium. The aim of this study was to determine if pretreatment with pravastatin would attenuate the acute renal dysfunction that occurs following IR injury in an experimental model.

Materials and methods. Male Sprague–Dawley rats were randomized into four groups (n = 7 per group): control, uninephrectomy, IR group, and IR group pretreated with pravastatin (0.4 mg/kg/day for the preceding 5 days). Following a left nephrectomy the IR injury was induced by cross-clamping the right vascular pedicle for 30 min followed by reperfusion for 2 h. In a separate experiment (n = 6 per group) renal function was assessed 12 and 24 h after reperfusion.

Results. IR injury causes significant renal dysfunction chacterized by oliguria, 0.11 (0.05) ml/h, decreased glomerular filtration rate (GFR), 0.02 (0.01) ml/min; and marked protein leakage, 7.21 (1.3) g/L, 2 h postreperfusion. This renal dysfunction was also evident 12 and 24 h postreperfusion. This was in contrast to values of 0.61 (0.13) ml/h, 0.23 (0.01) ml/min, and 1.67 (0.12) g/L in the uninephrectomy-only group and values of 2 ml/h, 7.3 ml/min, and 0.72 g/L for uninjured time-matched controls. Pretreatment with pravastatin significantly attenuated IR-induced renal injury, improving urine production to 0.62 (0.2) ml/h and GFR to 0.14 (0.02) ml/min and diminishing protein leakage to 3.76 (0.7) g/L at the 2-h time point. This renoprotective effect was also evident 12 and 24 h postreperfusion. This renal protection was associated with an upregulation of constitutive endothelial nitric oxide synthase in the pravastatin-treated group.

Conclusion. These results show that pravastatin may play a role in modulating renal impairment following aortic or transplantation surgery, allowing earlier recovery from an IR injury.

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IR-induced tissue injury which can be encountered during surgical interventions involving abdominal aorta (AA) is a complex process affecting lower extremities as well as remote tissues and organs like heart, liver, kidney, and lungs [1–4].
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A total of 30 adult male Wistar-Albino rats were equally and randomly separated to three groups as follows: SHAM laparotomy, ischemia-reperfusion (IR), and IR + IL-18BP. We applied 30-min IAO and 2-h reperfusion. Inflammatory cytokine levels (TNF-α, IL-1β, IL-18, IL-6, and IFN-γ) and oxidative stress parameters (TAS, TOS, and OSI) were measured. In addition to this, urea and creatinine levels, histopathology of kidney, mRNA expression levels of inflammatory cytokines, and apoptotic genes were investigated.
Urea and creatinine, tissue and serum levels of TNF-α, IL-6, IL-18, IFN-γ, and TOS, and oxidative stress index (OSI) were found significantly lower in IR + IL-18BP group, when compared to the IR group. Moreover, mRNA expression levels of inflammatory cytokines and apoptotic genes were prominently depressed in IR + IL-18BP pre-treatment group in histopathologic examination, there was a significant difference between the IR and other three groups (P < 0.001). These improvements were demonstrated with a total score of histopathologic damage. In our previous studies, we have demonstrated that IL-18BP has antioxidant, inflammatory, and protective effects on liver and spinal cord IR injury. Data established from the present study suggest that IL-18BP may exert anti-inflammatory, antiapoptotic, antioxidant, and protective effects on IAO-induced acute kidney injury in rats, and this would be the first study to be conducted in this field.
Data established from the present study suggest that IL-18BP may exert anti-inflammatory, antiapoptotic, antioxidant, and protective effects on IAO-induced acute kidney injury in rats.
N-Acetylcysteine and High-Dose Atorvastatin Reduce Oxidative Stress in an Ischemia-Reperfusion Model in the Rat Kidney
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Some authors have suggested that statins could suppress MPO expression [14] by down-regulating MPO gene expression in macrophages. Because of these properties, several studies have been conducted to test the effectiveness of statins in preventing IR injury and acute rejection episodes after transplantation [19,35,36]. To our knowledge, there are no studies specifically aimed at testing the effects of short-term treatment with high-dose statins and NAC in the setting of IR injury in the kidney.
To investigate the effects of N-acetylcysteine (NAC) and high-dose atorvastatin (ATOR) in reducing oxidative stress in a rat kidney model of ischemia-reperfusion injury.
Forty female rats underwent clamping of the left renal artery for 30 minutes, followed by reperfusion. The effects of pre-ischemic administration of NAC and/or ATOR were evaluated within 4 groups: a) control (no NAC, no ATOR); b) NAC (intraperitoneal NAC administration); c) ATOR (oral ATOR administration); and d) NAC+ATOR (both drugs). Oxidative stress was assessed by measuring the activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and myeloperoxidase (MPO). Post–ischemia-reperfusion injury was evaluated by means of renal histology.
NAC, ATOR, and NAC+ATOR in rats showed lower MPO (P < .05) and higher GPx activity (P < .05) versus control; SOD activity was lower in NAC versus ATOR (P < .05). No difference among groups was found at histology. However, a lower rate of tubular ischemic lesions was evident in NAC+ATOR versus control (P = .07).
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Association between preoperative statin use and acute kidney injury biomarkers in cardiac surgical procedures
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The predominant contributors to AKI in the setting of cardiac surgical procedures are thought to be ischemia and inflammation induced by cardiopulmonary bypass [3]. It is therefore biologically plausible that statins, which possess antiinflammatory properties and improve endothelial function, could prevent AKI associated with cardiac surgical procedures [5–9]. To our knowledge, our study is the first to examine the association of statins with kidney injury biomarkers.
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Continuing (vs holding) a statin before operation was not associated with a lower risk of AKI, as defined by a doubling of serum creatinine or dialysis (adjusted relative risk [RR] 1.09; 95% confidence interval [CI] 0.44, 2.70). However, continuing a statin was associated with a lower risk of elevation of the following AKI biomarkers: urine interleukin-18, urine neutrophil gelatinase-associated lipocalin, urine kidney injury molecule-1, and plasma neutrophil gelatinase-associated lipocalin (adjusted RR 0.34; 95% CI 0.18, 0.62), (adjusted RR 0.41; 95% CI 0.22, 0.76), (adjusted RR 0.37; 95% CI 0.20, 0.76), (adjusted RR 0.62; 95% CI 0.39, 0.98), respectively.
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^☆: This project was supported by a grant from the Royal College of Surgeons, Beaumont Hospital, Dublin 9, Ireland.

²: To whom correspondence and reprint requests should be addressed. Fax: 353-1-8370091. E-mail: [email protected].

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

Abstract

Ann. Vasc. Surg.

Transplant. Rev.

Kidney Int.

Lancet

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Kidney Int.

J. Biol. Chem.

Kidney Int.

Kidney Int.

J. Biol. Chem.

Acute renal failure following surgery for abdominal aortic aneurysm

Aust. N. Z. J. Surg.

Risk factors for postoperative death following elective surgical repair of abdominal aortic aneurysm: Results from the UK Small Aneurysm Trial

Br. J. Surg.

Ischemic injury during syngeneic rat kidney transplantation results in trafficking of inflammatory cells into the kidney and expression of major histocompatibility and adhesion molecules on renal tubule cells and capillary endothelium

J. Am. Soc. Nephrol.

Delayed graft function, acute rejection, and outcome after cadaver renal transplantation

Transplantation

Early function as the principal correlate of graft survival: A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine

Transplantation

Hyperplasia, hypertrophy, and phenotypic alterations in the distal nephron after acute proximal tubular injury in the rat

Lab. Invest.

Dissociation of tubular cell detachment and tubular cell death in clinical and experimental “acute tubular necrosis“

Lab. Invest.

Inhibition of cholesterol synthesis in vitro and in vivo by ML-236A and ML-236B, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Eur. J. Biochem.

Regulation of the mevalonate pathway

Nature

Lancet

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study

N. Engl. J. Med.

Reduction in cardiovascular events during pravastatin therapy

Circulation

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