Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium.

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.

Expression and role of peroxisome proliferator-activated receptors in the porcine early placenta trophoblast.

Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear receptor family of ligand-dependent transcription factors. Three isoforms of PPAR named PPARα, PPARß/δ, and PPARγ have been described, each encoded by a separate gene: PPARA, PPARD, and PPARG, respectively. In the present study, we examined the profiles of PPAR and retinoid X receptor (RXR; PPAR heterodimer partner) mRNA expression and PPAR DNA binding activity in porcine trophoblast tissue collected on days 15, 20, 25, and 30 of pregnancy and in day-20 embryos. Placenta trophoblast cells isolated on day 25 of pregnancy were used to determine effects of (1) cytokines on PPAR and RXR mRNA expression and (2) PPAR agonists on prostaglandin (PG) E2 synthesis and the expression of genes involved in steroidogenesis, fatty acid binding, and PG transport, as well as on cell proliferation. The mRNA expression of PPARA and RXRB was greater in trophoblast tissue collected on days 25 and 30 of pregnancy compared with day 15 (P < 0.05), while DNA binding activity of PPARα decreased between day 15 and 25 (P < 0.05). Increased concentrations of PPARD and RXRA transcripts were observed in trophoblasts collected on day 20 compared to trophoblasts from days 15 and 30 (P < 0.05). Moreover, concentrations of DNA-bound PPARß/δ and PPARγ proteins increased in day-30 trophoblasts compared to day 15 (P < 0.01) and day 20 (P < 0.05), respectively. On day 20 of gestation, the mRNA expression of PPARD, PPARG, and RXRA and protein levels of PPARα and PPARγ isoforms were greater in trophoblast than embryonic tissue (P < 0.01). Interleukin 1ß and/or interferon γ, but not IL6 and leukemia inhibitory factor, upregulated PPAR and RXR mRNA expression in placenta trophoblast cells in vitro (P < 0.05). Rosiglitazone (a PPARγ agonist) stimulated prostaglandin E synthase mRNA expression in trophoblast cells and PGE2 accumulation in incubation medium (P < 0.05). Moreover, activation of PPAR isoforms differentially affected the expression of genes involved in steroidogenesis, fatty acid binding, and PG transport in studied cells. Finally, PPARα and PPARγ agonists stimulated trophoblast cell proliferation (P < 0.05), and this effect was abolished by the addition of a respective PPAR antagonist (P < 0.05). Overall, these results point to a role of PPAR isoforms in porcine placenta development and function.

Regulation of expression and role of peroxisome proliferator-activated receptors (PPARs) in luminal epithelial and stromal cells of the porcine endometrium.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-dependent transcription factors. PPARs are important regulators of glucose and fatty acid metabolism, apoptosis, angiogenesis, cell proliferation and differentiation, and immune response. Their possible role in the female reproductive tract was demonstrated. In the present study, cultured luminal epithelial (LE) and stromal (ST) cells of the porcine endometrium were used to examine (1) the effect of conceptus exposed medium (CEM) on mRNA and protein expression and DNA binding activity of PPARA, PPARD, and PPARG isoforms, and (2) the effect of PPARA, PPARD, and PPARG agonists on the expression of selected genes, apoptosis, and cell proliferation. The addition of CEM stimulated PPARA expression and DNA binding activity of this isoform in LE and ST cells (P < 0.05). Increased expression of PPARD mRNA in the presence of CEM was detected in ST cells (P < 0.05), while the concentration of PPARG transcripts decreased in response to CEM in both cell types (P < 0.05). LE and ST cells of the pig endometrium possess PPARA, PPARD, and PPARG proteins, with clear nuclear staining visible predominately in ST cells. In LE cells, activation of PPARG with 15-deoxy-Δ12,14-prostaglandin(PG)J2 down-regulated the expression of genes encoding amino acid transporter 1 (SLC38A1), leukemia inhibitory factor (LIF) and enzymes involved in PG synthesis (P < 0.05). In ST cells, activation of PPARD isoform with both agonists used (L-165,041 and cPGI2) and PPARG isoform with 15-deoxy-Δ12,14-PGJ2 increased vascular endothelial growth factor A (VEGFA) mRNA expression (P < 0.05). Moreover, GW9578 (PPARA agonist) and 15-deoxy-Δ12,14-PGJ2 stimulated glucose transporter 1 (SLC2A1) gene expression in ST cells. 15-deoxy-Δ12,14-PGJ2 was also effective in up-regulation of the ratio of BAX/BCL2 mRNA expression and active caspase-3 concentration in ST cells (P < 0.05). Finally, GW9578 stimulated LE and ST cell proliferation, while rosiglitazone (PPARG agonist) increased the number of viable ST but not LE cells. In conclusion, this study demonstrated that conceptus products differentially modulate PPARs expression and activity in the porcine endometrium. Activation of PPARs may in turn affect nutrient transport, PG synthesis, angiogenesis, apoptosis, or cell proliferation in this tissue. Therefore, PPAR isoforms seem to play an important role in development and function of the porcine uterus.

Conserved transcriptional activity and ligand responsiveness of avian PPARs: Potential role in regulating lipid metabolism in mirgratory birds.

Migratory birds undergo metabolic remodeling in tissues, including increased lipid storage in white adipose and fatty acid uptake and oxidation in skeletal muscle, to optimize energy substrate availability and utilization in preparation for long-distance flight. Different tissues undergo gene expression changes in keeping with their specialized functions and driven by tissue specific transcriptional pathways. Peroxisome proliferator-activated receptors (PPARs) are lipid-activated nuclear receptors that regulate metabolic pathways involved in lipid and glucose utilization or storage in mammals. To examine whether PPARs might mediate fatty acid activation of metabolic gene programs that would be relevant during pre-migratory fattening, we used gray catbird as the focal species. PPAR isoforms cloned from catbird share high amino acid identity with mammalian homologs (% vs human): gcPPARα (88.1%), gcPPARδ (87.3%), gcPPARγ (91.2%). We tested whether gcPPARs activated fatty acid (FA) utilization genes using Lpl and Cpt1b gene promoter-luciferase reporters in mammalian cell lines. In C2C12 mouse myocytes gcPPARα was broadly activated by the saturated and unsaturated FAs tested; while gcPPARδ showed highest activation by the mono-unsaturated FA, 18:1 oleic acid (+80%). In CV-1 monkey kidney cells gcPPARγ responded to the poly-unsaturated fatty acid, 20:5 eicosapentaenoic acid (+60%). Moreover, in agreement with their structural conservation, gcPPARs were activated by isoform selective synthetic agonists similar to the respective mammalian isoform. Adenoviral mediated over-expression of PPARα in C2C12 myocytes induced expression of genes involved in fatty acid transport, including Cd36/Fat, as well as Cpt1b, which mediates a key rate limiting step of mitochondrial ß-oxidation. These gene expression changes correlated with increased lipid droplet accumulation in C2C12 myoblasts and differentiated myotubes and enhanced ß-oxidation in myotubes. Collectively, the data predict that the PPARs play a conserved role in gray catbirds to regulate lipid metabolism in target tissues that undergo metabolic remodeling throughout the annual migratory cycle.

The roles of PPARs in human diseases.

Peroxisome proliferator-activated receptors (PPARs), as members of nuclear hormone receptor superfamily, can be activated by binding natural or synthetic ligands. The use of related ligands has revealed many potential roles for PPARs in the pathogenesis of some human metabolic disorders and inflammatory-related disease. Based on the previous studies, this review primarily concluded the current progress of knowledge regarding the specific biological activity of PPARs in cancers, atherosclerosis, and type 2 diabetes mellitus, providing a foundation for the potential therapeutic use of PPAR ligands in human diseases.

Editor's Highlight: PPARß/δ and PPARγ Inhibit Melanoma Tumorigenicity by Modulating Inflammation and Apoptosis.

Skin tumorigenesis results from DNA damage, increased inflammation, and evasion of apoptosis. The peroxisome proliferator-activated receptors (PPARs) can modulate these mechanisms in non-melanoma skin cancer. However, limited data exists regarding the role of PPARs in melanoma. This study examined the effect of proliferator-activated receptor-ß/δ (PPARß/δ) and PPARγ on cell proliferation, anchorage-dependent clonogenicity, and ectopic xenografts in the UACC903 human melanoma cell line. Stable overexpression of either PPARß/δ or PPARγ enhanced ligand-induced expression of a PPARß/δ/PPARγ target gene in UACC903 cell lines as compared with controls. The induction of target gene expression by ligand activation of PPARγ was not altered by overexpression of PPARß/δ, or vice versa. Stable overexpression of either PPARß/δ or PPARγ reduced the percentage of cells in the G1 and S phase of the cell cycle, and increased the percentage of cells in the G2/M phase of the cell cycle in UACC903 cell lines as compared with controls. Ligand activation of PPARß/δ did not further alter the distribution of cells within each phase of the cell cycle. By contrast, ligand activation of PPARγ enhanced these changes in stable UACC903 cells overexpressing PPARγ compared with controls. Stable overexpression of either PPARß/δ or PPARγ and/or ligand activation of either PPARß/δ or PPARγ inhibited cell proliferation, and anchorage-dependent clonogenicity of UACC903 cell lines as compared with controls. Further, overexpression of either PPARß/δ or PPARγ and/or ligand activation of either PPARß/δ or PPARγ inhibited ectopic xenograft tumorigenicity derived from UACC903 melanoma cells as compared with controls, and this was likely due in part to induction of apoptosis. Results from these studies demonstrate the antitumorigenic effects of both PPARß/δ and PPARγ and suggest that targeting these receptors may be useful for primary or secondary melanoma chemoprevention.

Ginseng on Nuclear Hormone Receptors.

The first record of ginseng use dates back over two millennia, and ginseng is now popular in more than 35 countries. Ginsenosides are the pharmacological constituents responsible for the beneficial effects of ginseng. There is increasing evidence that ginseng and its bioactive ingredients are involved in the regulation of nuclear receptors, molecules that act in response to the specific binding of hormones, which link to a diverse array of signaling pathways, such as the ERK and PI3K/Akt pathways. Knowledge of the mechanism of how ginseng mediates these complexes is essential for the development of multi-target phytomedicine as possible therapy for different diseases. Here, we discuss the literature on the effects of ginseng and its constituents on estrogen, glucocorticoid, peroxisome proliferator-activated, and androgen nuclear hormone receptors, as well as how ginseng and its constituents exert their biological function in the treatment of cancer, obesity, and cardiovascular and neurological disorders. The accumulated results definitely show that the nuclear receptors are cellular targets of ginsenosides, but more rigorous data are required to establish and provide a scientific basis to confirm the suggested efficacy of ginseng or products with ginsenosides.

Bone marrow mesenchymal stem cells of the intrauterine growth-restricted rat offspring exhibit enhanced adipogenic phenotype.

OBJECTIVE: Although intrauterine nutritional stress is known to result in offspring obesity and the metabolic phenotype, the underlying cellular/molecular mechanisms remain incompletely understood. We tested the hypothesis that compared with the controls, the bone marrow-derived mesenchymal stem cells (BMSCs) of the intrauterine growth-restricted (IUGR) offspring exhibit a more adipogenic phenotype. METHODS: A well-established rat model of maternal food restriction (MFR), that is, 50% global caloric restriction during the later-half of pregnancy and ad libitum diet following birth that is known to result in an obese offspring with a metabolic phenotype was used. BMSCs at 3 weeks of age were isolated, and then molecularly and functionally profiled. RESULTS: BMSCs of the intrauterine nutritionally-restricted offspring demonstrated an increased proliferation and an enhanced adipogenic molecular profile at miRNA, mRNA and protein levels, with an overall up-regulated PPARγ (miR-30d, miR-103, PPARγ, C/EPBα, ADRP, LPL, SREBP1), but down-regulated Wnt (LRP5, LEF-1, ß-catenin, ZNF521 and RUNX2) signaling profile. Following adipogenic induction, compared with the control BMSCs, the already up-regulated adipogenic profile of the MFR BMSCs, showed a further increased adipogenic response. CONCLUSIONS: Markedly enhanced adipogenic molecular profile and increased cell proliferation of MFR BMSCs suggest a possible novel cellular/mechanistic link between the intrauterine nutritional stress and offspring metabolic phenotype. This provides new potential predictive and therapeutic targets against these conditions in the IUGR offspring.

MicroRNAs and Peroxisome Proliferator-Activated Receptors Governing the Differentiation of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) have the self-renewal ability and the ability to produce multiple differentiation. Elucidating the genetic circuits that govern MSC self-renewal and differentiation is necessary to improve our comprehension of MSCs and their role in regenerative medicine. microRNAs (miRNAs) play important roles in the regulation of transcription, and are strongly linked with MSCs regarding the maintenance of pluripotency properties. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormonereceptor family. Interestingly, PPARs not only regulate glucose metabolism and lipidhomeostasis, but also contribute to cell proliferation, cell differentiation, and cell apoptosis. The aim of the present review was to provide an insight into the roles of miRNAs and PPARs in the differentiation of MSCs. Understanding the miRNA signature interactions in conjunction with the role of PPARs is critical for the development of improved strategies to regulate the differentiation of MSCs.

Regulation of lipid metabolism and peroxisome proliferator-activated receptors in rainbow trout adipose tissue by lipolytic and antilipolytic endocrine factors.

The aim of this study was to determine the effects of growth hormone (GH) and insulin-like growth factor (IGF)-I on glycerol release and the regulation of IGF-I and IGF-II expression by GH in isolated rainbow trout adipocytes. Cells were also incubated with GH, tumor necrosis factor α (TNFα), or insulin to analyze the gene expression of peroxisome proliferator-activated receptors (PPARs) and lipid metabolism markers: hormone sensitive lipase, fatty acid synthase (FAS), and lipoprotein lipase. Complimentary in vivo experiments were performed by intraperitoneally administering insulin, TNFα, or lipopolysaccharide and subjecting the animals to fasting and refeeding periods. The results showed that IGF-I had an antilipolytic effect and GH had a lipolytic effect; the latter occurred independently of IGF modulation and in conjunction with a reduction in PPARα expression in adipocytes. The anabolic action of insulin was demonstrated through its upregulation of lipogenic genes such as lipoprotein lipase, FAS, and PPARγ, whereas GH, by contrast, inhibited FAS expression in adipose tissue. The gene transcription levels of PPARs changed differentially during fasting and refeeding, and the TNFα and/or lipopolysaccharide administration suggested that the regulation of PPARs helps maintain metabolic adipose tissue homeostasis in rainbow trout.

Impaired alveolarization and intra-uterine growth restriction in rats: a postnatal genome-wide analysis.

Intra-uterine growth restriction (IUGR) dramatically increases the risk of bronchopulmonary dysplasia in preterm babies, a disease characterized by arrested alveolarization and abnormal microvascular angiogenesis. We have previously described a rodent low protein diet (LPD) model of IUGR inducing impaired alveolarization, but failed to demonstrate any modification of the classical factors involved in lung development. We performed a genome-wide microarray analysis in 120 rat pups with LPD-induced IUGR and their controls, at three key time points of the alveolarization process: postnatal day 4 (P4): start of alveolarization; P10: peak of the alveolarization process and P21: end of the alveolarization process. Results were analysed using Arraymining, DAVID and KEGG software and validated by qRT-PCR and western blots. Considering a cut-off of 2:1 as significant, 67 transcripts at P4, 102 transcripts at P10 and 451 transcripts at P21 were up-regulated, and 89 transcripts at P4, 25 transcripts at P10 and 585 transcripts at P21 were down-regulated. Automatic functional classification identified three main modified pathways, 'cell adhesion molecules', 'cardiac muscle contraction' and 'peroxisome proliferator-activated receptor' (PPAR). Protein analysis confirmed involvement of the PPAR pathway, with an increase of FABP4, an activator of this pathway, at P4 and an increase of adiponectin at P21. Other data also suggest involvement of the PPAR pathway in impaired alveolarization. Our results show that deregulation of the PPAR pathway may be an important component of the mechanism inducing impaired alveolarization observed in IUGR. The complete dataset is available as GEO profiles on the Gene Expression Omnibus (GEO) database ( www.ncbi.nih.gov/geo/, GEO Accession No. GSE56956).

Modulation of VEGF-induced retinal vascular permeability by peroxisome proliferator-activated receptor-ß/δ.

PURPOSE: Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor ß/δ (PPARß/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARß/δ in VEGF-induced retinal hyperpermeability. METHODS: Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 were assayed by Western blot analysis. Expression of VEGFR1 and R2 was measured by quantitative RT-PCR. Last, retinal vascular permeability was assayed in vivo by Evans blue extravasation. RESULTS: Human retinal microvascular endothelial cell monolayers treated with VEGF for 24 hours showed decreased TEER values that were completely reversed by the highest concentration of GSK0660 (10 µM) and PPARß/δ-directed siRNA (20 µM). In HRMEC treated with VEGF, GSK0660 stabilized tight-junctions as evidenced by Claudin-1 staining, reduced phosphorylation of Erk1/2, and reduced VEGFR1/2 expression. Peroxisome proliferator-activated receptor ß/δ siRNA had a similar effect on VEGFR expression and Claudin-1, supporting the specificity of GSK0660 in our experiments. Last, GSK0660 significantly inhibited VEGF-induced retinal vascular permeability and reduced retinal VEGFR1and R2 levels in C57BL/6 mice. CONCLUSIONS: These data suggest a protective effect for PPARß/δ antagonism against VEGF-induced vascular permeability, possibly through reduced VEGFR expression. Therefore, antagonism/reverse agonism of PPARß/δ siRNA may represent a novel therapeutic methodology against retinal hyperpermeability and is worthy of future investigation.

Ischemia­reperfusion injury in patients with fatty liver and the clinical impact of steatotic liver on hepatic surgery.

Hepatic steatosis is one of the most common hepatic disorders in developed countries. The epidemic of obesity in developed countries has increased with its attendant complications, including metabolic syndrome and non-alcoholic fatty liver disease. Steatotic livers are particularly vulnerable to ischemia/reperfusion injury, resulting in an increased risk of postoperative morbidity and mortality after liver surgery, including liver transplantation. There is growing understanding of the molecular and cellular mechanisms and therapeutic approaches for treating ischemia/reperfusion injury in patients with steatotic livers. This review discusses the mechanisms underlying the susceptibility of steatotic livers to ischemia/reperfusion injuries, such as mitochondrial dysfunction and signal transduction alterations, and summarizes the clinical impact of steatotic livers in the setting of hepatic resection and liver transplantation. This review also describes potential therapeutic approaches, such as ischemic and pharmacological preconditioning, to prevent ischemia/reperfusion injury in patients with steatotic livers. Other approaches, including machine perfusion, are also under clinical investigation; however, many pharmacological approaches developed through basic research are not yet suitable for clinical application.

Cholesterol and male fertility: what about orphans and adopted?

The link between cholesterol homeostasis and male fertility has been clearly suggested in patients who suffer from hyperlipidemia and metabolic syndrome. This has been confirmed by the generation of several transgenic mouse models or in animals fed with high cholesterol diet. Next to the alteration of the endocrine signaling pathways through steroid receptors (androgen and estrogen receptors); "orphan" and "adopted" nuclear receptors, such as the Liver X Receptors (LXRs), the Proliferating Peroxisomal Activated Receptors (PPARs) or the Liver Receptor Homolog-1 (LRH-1), have been involved in this cross-talk. These transcription factors show distinct expression patterns in the male genital tract, explaining the large panel of phenotypes observed in transgenic male mice and highlighting the importance of lipid homesostasis and the complexity of the molecular pathways involved. Increasing our knowledge of the roles of these nuclear receptors in male germ cell differentiation could help in proposing new approaches to either treat infertile men or define new strategies for contraception.

Nuclear receptor mediated mechanisms of macrophage cholesterol metabolism.

Macrophages comprise a family of multi-faceted phagocytic effector cells that differentiate "in situ" from circulating monocytes to exert various functions including clearance of foreign pathogens as well as debris derived from host cells. Macrophages also possess the ability to engulf and metabolize lipids and this way connect lipid metabolism and inflammation. The molecular link between these processes is provided by certain members of the nuclear receptor family. For instance, peroxisome proliferator activated receptors (PPAR) and liver X receptors (LXR) are able to sense the dynamically changing lipid environment and translate it to gene expression changes in order to modulate the cellular phenotype. Atherosclerosis embodies both sides of this coin: it is a disease in which macrophages with altered cholesterol metabolism keep the arteries in a chronically inflamed state. A large body of publications has accumulated during the past few decades describing the role of nuclear receptors in the regulation of macrophage cholesterol homeostasis, their contribution to the formation of atherosclerotic plaques and their crosstalk with inflammatory pathways. This review will summarize the most recent findings from this field narrowly focusing on the contribution of various nuclear receptors to macrophage cholesterol metabolism.

TNF-α increases lipogenesis via JNK and PI3K/Akt pathways in SZ95 human sebocytes.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is an important pathophysiologic factor involved in the development of acne. However, its role is unclear. OBJECTIVE: To explore the lipogenic effect by TNF-α and possible molecular mechanisms in sebocyte. METHODS: Using SZ95 human sebocytes, lipid formation by TNF-α was assessed by Oil Red O, Nile Red staining and thin layer chromatography (TLC). Expression of lipogenic genes and activation of mitogen-activated protein kinase as well as Akt were examined by real-time polymerase chain reaction and/or Western blot analysis. Activation of peroxisome proliferator-activated receptor (PPAR) was evaluated by luciferase assay using PPAR response element containing reporter plasmids. Involvement of c-Jun N-terminal kinase (JNK) and Akt in TNF-α-induced lipogenesis was investigated by molecule specific small interfering RNA and inhibitors. RESULTS: TNF-α treatment significantly increased formation of lipid droplets in accordance with up-regulated expression of FAS and activation of SREBP-1, but not PPARs. Suppression of phosphorylated JNK by the JNK inhibitor SP600125 greatly diminished TNF-α-induced expression of FAS and SREBP-1. TNF-α could not induce both expression of lipogenic proteins and lipid synthesis when Akt expression was attenuated with siRNA. CONCLUSIONS: TNF-α induces lipogenesis in SZ95 human sebocytes through the JNK and phosphoinositide-3-kinase/Akt pathways. These results will be valuable in developing therapeutic strategies for control of seborrhea and acne.

Inflammatory links between obesity and metabolic disease.

The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity. This has led to a convergence of the fields of immunology and nutrient physiology and the understanding that they are inextricably linked. The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases. In this Review, we highlight the cellular and molecular mechanisms at play in the generation of obesity-induced inflammation. We also emphasize how defining the immune regulation in metabolic tissues has broadened the understanding of the diversity of inflammatory responses.

Pathogenesis of acute kidney injury: foundation for clinical practice.

The pathogenesis of acute kidney injury (AKI) is complex, involving such factors as vasoconstriction, leukostasis, vascular congestion, cell death, and abnormal immune modulators and growth factors. Many targeted clinical therapies have failed, are inconclusive, or have yet to be tested. Given the complexity of the pathogenesis of AKI, it may be naive to expect that one therapeutic intervention would have success. Some examples of detrimental processes that can be blocked in preclinical models to improve kidney function and survival are apoptotic cell death in tubular epithelial cells, complement-mediated immune system activation, and impairment of cellular homeostasis and metabolism. Modalities with the potential to decrease morbidity and mortality in patients with AKI include vasodilators, growth factors, anti-inflammatory agents, and cell-based therapies. Pharmacologic agents that target these diverse pathways are being used clinically for other indications. Using combinatorial approaches in future clinical trials may improve our ability to prevent and treat AKI.

[Drug-induced hepatic injury, the challenge for cause investigation].

This report is the story of the long journey to identify the mechanism of fulminant hepatitis by the antigout drug, Benzbromarone. As soon as the 8th gout patient prescribed Benzbromarone (Benz) died of fulminant hepatitis in 20 years, the letter was sent to doctors identifying it as the causative agent in February 2000. At that time, Benz had been prescribed to 350,000 patients/year for 20 years. Is Benz the real cause of fulminant hepatitis? 1. Benz is a PPARa agonist like fenofibrate, and not a PPARgamma like troglitazone. 2. Troglitazone and Allopurinol have shown apoptosis in a human primary hepatocyte culture with the DNA laddering method, but Benz has not. 3. It was reported in 1979 that benzarone is a metabolite dissociated from two Br bases of Benz, but Walter et al. reported in 1987 that the Br base was not dissociated. Benzarone was not produced by an in vitro study with human S-9 and by an in vivo clinical study of Japanese volunteers. 4. The main metabolite of Benz in humans is 6-OH Benz, which has URAT-1 activity, like Benz. 5. It has been newly discovered that CYP2C9 is only one hepatic metabolism enzyme of Benz. 6. The rate of poor metabolizers of CYP2C9*3 (homozygous) in Japan is 1/2500, meanwhile, the rate of fulminant hepatitis at this time is 8 patients in 20 years, with 350,000 patients/year; therefore, it is difficult to view poor metabolizers as the cause. 7. Hepatic injury by Benz is an idiosyncrasy, the same as with many other drugs.