Growth hormone treatment in the pre-transplant period is associated with superior outcome after pediatric kidney transplantation.

BACKGROUND: Recombinant human growth hormone (rhGH) is frequently used for treatment of short stature in children with chronic kidney disease (CKD) prior to kidney transplantation (KT). To what extent this influences growth and transplant function after KT is yet unknown. METHODS: Post-transplant growth (height, sitting height, leg length) and clinical parameters of 146 CKD patients undergoing KT before the age of 8 years, from two German pediatric nephrology centers, were prospectively investigated with a mean follow-up of 5.56 years. Outcome in patients with (rhGH group) and without (non-prior rhGH group) prior rhGH treatment was assessed by the use of linear mixed-effects models. RESULTS: Patients in the rhGH group spent longer time on dialysis and less frequently underwent living related KT compared to the non-prior rhGH group but showed similar height z-scores at the time of KT. After KT, steroid exposure was lower and increments in anthropometric z-scores were significantly higher in the rhGH group compared to those in the non-prior rhGH group, although 18% of patients in the latter group were started on rhGH after KT. Non-prior rhGH treatment was associated with a faster decline in transplant function, lower hemoglobin, and higher C-reactive protein levels (CRP). After adjustment for these confounders, growth outcome did statistically differ for sitting height z-scores only. CONCLUSIONS: Treatment with rhGH prior to KT was associated with superior growth outcome in prepubertal kidney transplant recipients, which was related to better transplant function, lower CRP, less anemia, lower steroid exposure, and earlier maturation after KT. A higher resolution version of the Graphical abstract is available as Supplementary information.

The role of the gut microbiota and microbial metabolites in neuroinflammation.

Recent literature indicates a potential importance of the gut microbiota for immune-mediated diseases. For instance, decreased diversity of commensals or an outgrowth of some bacterial strains, referred to as gut dysbiosis, was recently linked to hypertension, colitis, lupus, rheumatoid arthritis, and multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) as pivotal animal model of MS revealed a potential importance of microbial metabolites, including short-chain fatty acids or tryptophan metabolites. Both metabolites may influence the disease by modulation of the immune system, mainly by inducing Treg. These studies prompted researchers to investigate the contribution of the gut microbiota and microbial metabolites in the pathogenesis of MS. This review summarizes recent findings on the gut microbiota in MS patients and discusses the potential mechanisms how microbial metabolites may affect neuroinflammation. Many of these studies have been performed in the EAE model and were later reversely translated to humans. We also give a short summary on dietary high-salt effects on microbiota components and discuss the potential relevance of high-salt as a risk factor in MS.

Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study.

AIMS: Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. METHODS AND RESULTS: The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. CONCLUSIONS: The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. TRIAL REGISTRATION: The study was registered at clinicalTrials.gov (NCT03129503).

Activation of Peroxisome Proliferator-Activated Receptor-δ as Novel Therapeutic Strategy to Prevent In-Stent Restenosis and Stent Thrombosis.

OBJECTIVE: Drug-eluting coronary stents reduce restenosis rate and late lumen loss compared with bare-metal stents; however, drug-eluting coronary stents may delay vascular healing and increase late stent thrombosis. The peroxisome proliferator-activated receptor-delta (PPARδ) exhibits actions that could favorably influence outcomes after drug-eluting coronary stents placement. APPROACH AND RESULTS: Here, we report that PPARδ ligand-coated stents strongly reduce the development of neointima and luminal narrowing in a rabbit model of experimental atherosclerosis. Inhibition of inflammatory gene expression and vascular smooth muscle cell (VSMC) proliferation and migration, prevention of thrombocyte activation and aggregation, and proproliferative effects on endothelial cells were identified as key mechanisms for the prevention of restenosis. Using normal and PPARδ-depleted VSMCs, we show that the observed effects of PPARδ ligand GW0742 on VSMCs and thrombocytes are PPARδ receptor dependent. PPARδ ligand treatment induces expression of pyruvate dehydrogenase kinase isozyme 4 and downregulates the glucose transporter 1 in VSMCs, thus impairing the ability of VSMCs to provide the increased energy demands required for growth factor-stimulated proliferation and migration. CONCLUSIONS: In contrast to commonly used drugs for stent coating, PPARδ ligands not only inhibit inflammatory response and proliferation of VSMCs but also prevent thrombocyte activation and support vessel re-endothelialization. Thus, pharmacological PPARδ activation could be a promising novel strategy to improve drug-eluting coronary stents outcomes.

A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

Deep Learning Based Automatic Fibroglandular Tissue Segmentation in Breast Magnetic Resonance Imaging Screening.

In light of the global increase in breast cancer cases and the crucial importance of the density of fibroglandular tissue (FGT) in assessing risk and predicting the course of the disease, the accurate measurement of FGT emerges as a significant challenge in diagnostic imaging. The current study focuses on the automatic segmentation of breast glandular tissue in MRI scans using a deep learning model. The aim is to establish a solid foundation for the development of methods for the precise quantification of fibroglandular tissue. For this purpose, the publicly available 'Duke Breast Cancer MRI' dataset was systematically processed to train a deep neural network model utilizing the nnU-Net ('no-new-Net') framework, which was then subjected to a quantitative evaluation. The results show the following macro-averaged metrics with standard deviation: Dice Similarity Coefficient 0.827 ± 0.152, accuracy 0.997 ± 0.003, sensitivity 0.825 ± 0.158, and specificity 0.999 ± 0.001. The effectiveness of our model in segmenting FGT is underscored by the high values of the Dice coefficient, Accuracy, Sensitivity, and Specificity, which reflect the precision and reliability of our results. The findings of this study lay a solid foundation for developing automated methods to quantify FGT. Our research efforts, especially driven by clinical studies at the University Hospital Augsburg, are focused on further exploring and validating these potentials.

Towards Automated COVID-19 Presence and Severity Classification.

COVID-19 presence classification and severity prediction via (3D) thorax computed tomography scans have become important tasks in recent times. Especially for capacity planning of intensive care units, predicting the future severity of a COVID-19 patient is crucial. The presented approach follows state-of-theart techniques to aid medical professionals in these situations. It comprises an ensemble learning strategy via 5-fold cross-validation that includes transfer learning and combines pre-trained 3D-versions of ResNet34 and DenseNet121 for COVID19 classification and severity prediction respectively. Further, domain-specific preprocessing was applied to optimize model performance. In addition, medical information like the infection-lung-ratio, patient age, and sex were included. The presented model achieves an AUC of 79.0% to predict COVID-19 severity, and 83.7% AUC to classify the presence of an infection, which is comparable with other currently popular methods. This approach is implemented using the AUCMEDI framework and relies on well-known network architectures to ensure robustness and reproducibility.

Anti-ß1-Adrenoreceptor auto-Antibodies in elderly heart failure patients.

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (beta1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like beta1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect beta 1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate beta 1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) less than 50% or LV diameter end diastolic (DED) more than 55 cm showed significantly higher levels of beta1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of beta1-ADR-AA with the EF at baseline and at the follow up, beta1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. beta1-ADR-AA levels thus determined  significantly increased under titration with beta-blockers (pless  than 0.01). Changes in beta1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.016) before study inclusion. The type of beta-blocker titrated in this study did not affect log beta1-ADR-AA levels at baseline (p=0.132), follow-up (p=0.058), nor the change (p=0.426). beta1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless  than 0.01), irrespective of type of BB. Higher levels of beta1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the beta1-ADR-AA biomarker should be further evaluated.

Soluble (pro)renin receptor in preeclampsia and diabetic pregnancies.

Women with preexisting or gestational diabetes mellitus have an increased risk for developing preeclampsia. Diabetes and pregnancy are both characterized by very high prorenin levels and renin-angiotensin system activation. Prorenin bound to the (pro)renin receptor has enzymatic activity. We hypothesized that soluble (pro)renin receptor levels are elevated in high-risk pregnancies. Third trimester maternal blood samples from complicated pregnancies (n = 165), (preeclampsia [n = 76], diabetes mellitus [type I diabetes, n = 35; type II diabetes, n = 11; gestational diabetes mellitus, n = 43]), and healthy pregnancies (n = 49) were analyzed for prorenin, renin, and soluble (pro)renin receptor. There were no significant differences in prorenin or renin levels between the study groups in a multivariate model. In the group of women with gestational diabetes, soluble (pro)renin receptor concentrations were significantly higher compared with healthy pregnancies or preeclampsia. Soluble (pro)renin receptor did not correlate with renin or prorenin levels for any of the study groups. Our results show that soluble (pro)renin receptor is dysregulated in pregnancies affected by diabetes mellitus, but not in preeclampsia. Alterations in circulating soluble (pro)renin receptor are unrelated to renin/prorenin in pregnancy, but may be of pathophysiological relevance in diabetic pregnancies in a renin-angiotensin system-independent manner.

Biokinetics of Aerosolized Liposomal Ciclosporin A in Human Lung Cells In Vitro Using an Air-Liquid Cell Interface Exposure System.

BACKGROUND: Inhalation of aerosolized drugs is a promising route for noninvasive targeted drug delivery to the lung. Nanocarrier systems such as liposomes have been explored for inhalation therapy opening new avenues, including stabilization of nonsoluble drugs (e.g., Ciclosporin A [CsA]) and controlled release. METHODS: The biokinetic behavior of the immunosuppressive drug CsA encapsulated in liposomes (L-CsA) at the lung epithelial barrier was studied in vitro. Human lung epithelial cells (alveolar A549 and bronchial 16HBE14o- epithelial cells) were exposed to aerosolized L-CsA at the air-liquid interface (ALI) using a dose-controlled air-liquid interface cell exposure (ALICE) system and the temporal profile of the L-CsA dose in the apical, basal, and cell compartment was monitored up to 24 hours. RESULTS: Aerosolization of different volumes of L-CsA solution with the ALICE resulted in dose-controlled, spatially uniform, and reproducible L-CsA delivery. Cell viability at 24 hours postexposure was not impaired and immunofluorescence staining revealed the typical epithelial cell morphology in control as well as in L-CsA-exposed cells. The (pro-)inflammatory interleukin-8 levels were not elevated under any condition. The biokinetic analysis revealed that both cell types formed a tight, but imperfect, barrier for L-CsA resulting in initially high transbarrier L-CsA transport rates, which ceased after about 4 hours. Although substantial transbarrier L-CsA transport was observed for both cell types, respectively, a 150-fold higher L-CsA concentration was established in the apical and cell compared to the basal compartment. Most importantly, for pulmonary drug targeting, a high cellular L-CsA dose level (20%-25% of the delivered dose) was obtained rapidly (<1 hour) and maintained for at least 24 hours. CONCLUSIONS: The ALICE system combined with lung epithelial cells cultured at the ALI offers a reliable and relevant in vitro platform technology to study the effects of inhalable substances such as L-CsA under biomimetic conditions.

Angiotensin IV is induced in experimental autoimmune encephalomyelitis but fails to influence the disease.

In multiple sclerosis (MS) and its corresponding animal models, over-activity of the renin-angiotensin system (RAS) has been reported and pharmacological RAS blockade exerts beneficial effects. The RAS generates a number of bioactive angiotensins, thereby primarily regulating the body's sodium homeostasis and blood pressure. In this regard, angiotensin IV (AngIV), a metabolite of the RAS has been shown to modulate inflammatory responses. Here we studied potential implications of AngIV signalling in myelin oligodendrocyte glycoprotein (MOG) peptide induced murine experimental autoimmune encephalomyelitis (EAE), a close-to-MS animal model. Mass spectrometry revealed elevated plasma levels of AngIV in EAE. Expression of cognate AT4 receptors was detected in macrophages and T cells as major drivers of pathology in EAE. Yet, AngIV did not modulate macrophage or T cell functions in vitro or displayed detectable effects on neuroantigen specific immune responses in vivo. The data argue against a major contribution of AngIV signalling in the immunopathogenesis of MOG-EAE.

Long-term follow-up of patients with atherosclerotic renal artery disease.

Atherosclerotic renal artery stenosis (ARAS) is a predictor of increased morbidity and mortality. However, whether ARAS itself accelerates the arteriosclerotic process or whether ARAS is solely the consequence of atherosclerosis is unclear. We imaged renal arteries of 1561 hypertensive patients undergoing coronary angiography and followed this cohort for 9 years (range, 2.4-15.1 years; median, 31.2 months, interquartile range, 13.4/52.9 months). All patients received aspirin, renin-angiotensin system blockade, statins, and beta blockade as indicated. One hundred seventy-one patients had ARAS >50% diameter stenosis and 126 patients an arteriosclerotic plaque (ARAP) without significant stenosis. Blood pressures were not different in ARAS, ARAP, and non-ARAS patients. After adjustment for cardiovascular risk factors by propensity scores and matched pair analysis, ARAS patients had a lower ejection fraction and more coronary artery disease (CAD) than non-ARAS patients. The same was true for brain natriuretic peptide values, troponin I, and highly sensitive C-reative protein. Over 9 years, more ARAS patients died of any cause (34% vs 23%; P < .05). The prevalence of CAD in ARAP patients was higher than in non-ARAS patients and lower than in ARAS patients. The mortality of the ARAP patients at 9 years was 37%, not different from the ARAS patients. Atherosclerotic renal artery disease appears to be a marker for the severity of atherosclerosis rather than a causative factor for atherosclerosis progression.

Inhibition of the renin-angiotensin-aldosterone system: is there room for dual blockade in the cardiorenal continuum?

Antagonism of renin-angiotensin-aldosterone system is exerted through angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, renin inhibitors and mineralocorticoid receptor antagonists. These drugs have been successfully tested in numerous trials and in different clinical settings. The original indications of renin-angiotensin-aldosterone system blockers have progressively expanded from the advanced stages to the earlier stages of cardiorenal continuum. To optimize the degree of blockade of renin-angiotensin-aldosterone system, dose uptitrations of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists or the use of a dual blockade, initially identified with the combination of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, have been proposed. The data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study do not support this specific dual blockade approach. However, the dual blockade of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists with direct renin inhibitors is currently under investigation while that based on an aldosterone blocker with any of the previous three drugs requires more evidence beyond heart failure. In this review, we revisited potential advantages of dual blockade of renin-angiotensin-aldosterone system in arterial hypertension and diabetes.

Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG(mRen-2)27 rats.

The aim of this study was to explore the effects of the renin inhibitor aliskiren in streptozotocin-diabetic TG(mRen-2)27 rats. Furthermore, we investigated in vitro the effect of aliskiren on the interactions between renin and the (pro)renin receptor and between aliskiren and prorenin. Aliskiren distributed extensively to the kidneys of normotensive (non)diabetic rats, localizing in the glomeruli and vessel walls after 2 hours exposure. In diabetic TG(mRen-2)27 rats, aliskiren (10 or 30 mg/kg per day, 10 weeks) lowered blood pressure, prevented albuminuria, and suppressed renal transforming growth factor-beta and collagen I expression versus vehicle. Aliskiren reduced (pro)renin receptor expression in glomeruli, tubules, and cortical vessels compared to vehicle (in situ hybridization). In human mesangial cells, aliskiren (0.1 micromol/L to 10 micromol/L) did not inhibit binding of (125)I-renin to the (pro)renin receptor, nor did it alter the activation of extracellular signal-regulated kinase 1/2 by renin (20 nmol/L) preincubated with aliskiren (100 nmol/L) or affect gene expression of the (pro)renin receptor. Evidence was obtained that aliskiren binds to the active site of prorenin. The above results demonstrate the antihypertensive and renoprotective effects of aliskiren in experimental diabetic nephropathy. The evidence that aliskiren can reduce in vivo gene expression for the (pro)renin receptor and that it may block prorenin-induced angiotensin generation supports the need for additional work to reveal the mechanism of the observed renoprotection by this renin inhibitor.

Effect of catheter-based transendocardial delivery of stromal cell-derived factor 1alpha on left ventricular function and perfusion in a porcine model of myocardial infarction.

BACKGROUND: Myocardial regeneration after myocardial infarction can occur via stem cell recruitment. Stromal cell-derived factor 1alpha (SDF-1alpha) has been shown to be critical for stem cell homing to injured tissue. METHODS: Myocardial infarction was induced in pigs via microembolization of the distal left anterior descending artery. Two weeks after myocardial infarction animals underwent catheter-based transendocardial injection of SDF-1alpha into the periinfarct myocardium (18 injections, 5 ìg per injection) (n = 12) or sham-intervention (n = 8). Tc99m sestamibi single-photon emission computed tomography (SPECT) and electromechanical mapping (EMM) of the left ventricle were performed two and seven weeks after myocardial infarction. RESULTS: Infarct size by tetrazolium staining was similar in both groups (8.9 +/-1.2% of left ventricle vs. 8.9 +/- 2.6%). Vessel density in the periinfarct area was significantly higher in SDF-1alpha treated animals than in controls (349 +/- 17/mm2 vs. 276 +/- 21/mm2, p < 0.05). Myocardial perfusion (SPECT) did not change in either group. Ejection fraction and stroke volume (EMM) decreased in SDF-1alpha animals and increased in controls (difference between groups p = 0.05 for ejection fraction and p < 0.05 for stroke volume). Linear local shortening (EMM) did not change in controls (11.4 +/- 1.3% to 11.5 +/- 0.5%) but decreased significantly in SDF-1alpha treated animals (12.1 +/- 0.9% to 8.4 +/- 0.9%, p < 0.05, p < 0.05 for difference between groups). SDF-1 delivery was associated with a substantial loss of collagen in the periinfarct area (32+/-5% vs. 61+/-6% in control animals, p < 0.005). CONCLUSION: A strategy to augment stem cell homing by catheter-based transendocardial delivery of SDF-1alpha in experimental myocardial infarction increases periinfarct vessel density, fails to improve myocardial perfusion, is associated with loss of collagen in the periinfarct area and impairs left ventricular function.

Postischemic acute renal failure is reduced by short-term statin treatment in a rat model.

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.