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At least 307 records · Page 17Linked to original sources
PubMed2002

Mdm2 overexpression and p14(ARF) inactivation are two mutually exclusive events in primary human lung tumors.

Pathways involving p53 and pRb tumor suppressor genes are frequently deregulated during lung carcinogenesis. Through its location at the interface of these pathways, Mdm2 can modulate the function of both p53 and pRb genes. We have examined here the pattern of expression of Mdm2 in a series of 192 human lung carcinomas of all histological types using both immunohistochemical and Western blot analyses and four distinct antibodies mapping different epitopes onto the Mdm2 protein. Using Immunohistochemistry (IHC), Mdm2 was overexpressed as compared to normal lung in 31% (60 out of 192) of all tumors analysed, whatever their histological types. Western blotting was performed on 28 out of the 192 tumoral samples. Overexpression of p85/90, p74/76 and p57 Mdm2 isoforms was detected in 18% (5 out of 28), 25% (7 out of 28) and 39% (11 out of 28) of the cases respectively. Overall, overexpression of at least one isoform was observed in 14 out of 28 (50%) lung tumors and concomittant overexpression of at least two isoforms in 7 out of 28 (25%) cases. A good concordance (82%) was observed between immunohistochemical and Western blot data. Interestingly, a highly significant inverse relationship was detected between p14(ARF) loss and Mdm2 overexpression either in NSCLC (P=0.0089) or in NE lung tumors (P<0.0001). Furthermore, a Mdm2/p14(ARF) >1 ratio was correlated with a high grade phenotype among NE tumors overexpressing Mdm2 (P=0.0021). Taken together, these data strongly suggest that p14(ARF)and Mdm2 act on common pathway(s) to regulate p53 and/or pRb-dependent or independent functions and that the Mdm2 : p14(ARF) ratio might act as a rheostat in modulating the activity of both proteins.

Biomarkers, Tumor↗
PubMed2004

Stability of nucleolar versus non-nucleolar forms of human p14(ARF).

Fusion proteins containing the amino-terminal domain of human p14(ARF) linked to green fluorescent protein are able to bind MDM2 and stabilize p53 without localization in the nucleolus. However, these fusion proteins are inherently unstable, with half-lives considerably shorter than either authentic ARF or chimaeras containing the entire coding domain, both of which are predominantly nucleolar. We present evidence that the unstable fusion proteins are significantly stabilized if redirected to the nucleolus by addition of a basic motif based on the nuclear localization signal of SV40 T-antigen. Moreover, the stability of these proteins can be enhanced by modulating the functions of MDM2 and p53. These data are consistent with a model in which ARF interacts with MDM2 in the nucleoplasm but is consequently subject to proteasomal degradation. Nucleolar localization may serve to store or stabilize ARF.

Base Sequence↗
PubMed2006

E2F1 suppresses skin carcinogenesis via the ARF-p53 pathway.

The E2F1 transcription factor, which is deregulated in most human cancers by mutations in the p16-cyclin D-Rb pathway, has both oncogenic and tumor-suppressive properties. This is dramatically illustrated by the phenotype of an E2F1 transgenic mouse model that spontaneously develops tumors in the skin and other epithelial tissues but is resistant to papilloma formation when subjected to a two-stage carcinogenesis protocol. Here, this E2F1 transgenic model was used to further explore the tumor-suppressive property of E2F1. Transgenic expression of E2F1 was found to inhibit ras-driven skin carcinogenesis at the promotion stage independent of the type of promoting agent used. E2F1 transgenic epidermis displayed increased expression of p19(ARF), p53, and p21(Cip1). Inactivation of either p53 or Arf in E2F1 transgenic mice restored sensitivity to two-stage skin carcinogenesis. While Arf inactivation impaired tumor suppression and p21 induction by E2F1, it did not reduce the level of apoptosis observed in E2F1 transgenic mice. Based on these findings, we propose that E2F1 suppresses ras-driven skin carcinogenesis through a nonapoptotic mechanism involving ARF and p53.

Animals↗
PubMed2005

The Arf-like GTPase Arl1 and its role in membrane traffic.

Small GTP-binding proteins of the Rab and Arf (ADP-ribosylation factor) families play a central role in the membrane trafficking pathways of eukaryotic cells. The prototypical members of the Arf family are Arf1-Arf6 and Sar1, which have well-characterized roles in membrane traffic or cytoskeletal reorganization. However, eukaryotic genomes encode additional proteins, which share the characteristic structural features of the Arf family, but the role of these 'Arf-like' (Arl) proteins is less well understood. This review discusses Arl1, a GTPase that is widely conserved in evolution, and which is localized to the Golgi in all species so far examined. The best-characterized effectors of Arl1 are coiled-coil proteins which share a C-terminal GRIP domain, but other apparent effectors include the GARP (Golgi-associated retrograde protein)/VFT (Vps fifty-three) vesicle-tethering complex and Arfaptin 2. As least some of these proteins are believed to have a role in membrane traffic. Genetic analysis in a number of species has shown that Arl1 is not essential for exocytosis, but rather suggest that it is required for traffic from endosomes to the Golgi.

ADP-Ribosylation Factors↗
PubMed2002

Germline and somatic mutations of the INK4a-ARF gene in a xeroderma pigmentosum group C patient.

Xeroderma pigmentosum is an inheritable autosomal recessive DNA repair deficient syndrome characterized by a high predisposition to skin cancers. An elevated proportion of tumors from xeroderma pigmentosum patients harbor ultraviolet-induced mutations (CC:GG > TT:AA tandem transitions) of the p53 and/or the INK4a-ARF genes. Here, we report the clinical and molecular features of a 12 y old xeroderma pigmentosum patient who, in addition to severe cutaneous clinical symptoms, also had three unusual tumors, a mediastinal lymphoblastic lymphoma, an atypical fibroxanthoma, and an epithelioid hemangioma. Single strand conformation polymorphism and sequencing analysis of the p53 and INK4a-ARF genes were carried out in DNA from normal skin and different tumors (four actinic keratosis, two microinvasive squamous cell carcinomas, one basal cell carcinoma, and one atypical fibroxanthoma) from the patient. After characterization of the xeroderma pigmentosum C complementation group, we found unexpectedly that this patient also carried a germline mutation of the INK4a-ARF locus affecting the p16INK4A reading frame. Three different somatic mutations that all harbor the signature of ultraviolet light (two of p16INK4A and one of p53) were also detected in the basal cell carcinoma. We hypothesize that the germline mutation of p16INK4A, in association with the nucleotide excision repair defect, could explain the patient's unusual phenotype. Furthermore, this study confirms that concomitant somatic mutations of INK4a-ARF and p53 occur in some xeroderma pigmentosum associated tumors, and seem to accumulate during tumor progression rather than the initiation step.

Basal Cell Carcinoma↗
PubMed2003

High frequency of ultraviolet mutations at the INK4a-ARF locus in squamous cell carcinomas from psoralen-plus-ultraviolet-A-treated psoriasis patients.

Squamous cell carcinomas in psoralen-plus-ultraviolet A (PUVA) treated patients frequently exhibit p53 tumor suppressor genes and Ha-ras protooncogenes that are mutated at dipyrimidine sites and carry the ultraviolet fingerprint (i.e., C-to-T or CC-to-TT transitions). To further broaden the knowledge of genetic mutations in PUVA-associated skin cancer, we used DNA sequencing analysis to study the mutational spectrum of the INK4a-ARF locus in 26 squamous cell carcinomas from 11 long-term PUVA-treated psoriasis patients and classified the mutations by origin (ultraviolet, ultraviolet and/or PUVA, or other). Nineteen INK4a-ARF missense/nonsense mutations were found in exons 1alpha, 1beta, and 2 in 11 of 26 squamous cell carcinomas (42%) from seven of 11 patients (64%). Eleven mutations (58%) were of the ultraviolet type; three (16%) were of the ultraviolet and/or PUVA type (i.e., C-to-T transitions at dipyrimidine sites opposite a 5'TpG sequence, a potential psoralen binding site); and five (26%) were of other type. Interestingly, 10 of 11 patients (91%) showed intron polymorphism C500G at the 3' untranslated region of exon 3. These data indicate that (i) INK4a-ARF mutations frequently occur in PUVA-associated squamous cell carcinomas; (ii) ultraviolet B radiation is the major cause of these mutations; and (iii) PUVA itself may play no direct role in development of most INK4a-ARF mutations.

Adult↗
PubMed2003

Two male siblings with hereditary renal hypouricemia and exercise-induced ARF.

Familial renal hypouricemia with exercise-induced acute renal failure (ARF) is rare. A 45-year-old man presented with abdominal pain, vomiting, and oliguria after severe exercise. The diagnosis was ARF based on high serum creatinine (SCr) level (5.1 mg/dL [451 micromol/L]). Renal function recovered completely within 2 weeks of conservative treatment (creatinine clearance [Ccr], 100.4 mL/min [1.67 mL/s]). After remission, laboratory results showed serum urate (SUA) of 0.8 mg/dL (48 micromol/L), and fractional excretion of uric acid (FE(UA)) of 46%. The final diagnosis was ARF associated with idiopathic renal hypouricemia. Other diseases that could increase the excretion of urate were excluded. Because only mild responses were observed both in pyradinamide and benzbromarone loading tests, he was considered to be a presecretory reabsorption disorder type. The younger brother (42 years old) also had episodes of low and middle back pain after severe exercise and experienced similar attacks at least 5 times since the age of 29. SCr level was elevated in every attack. Hypouricemia (SUA, 1.0 mg/dL [59 micromol/L]) and high urinary urate excretion (FE(UA), 65.7%) also were detected. Renal function recovered almost completely without any specific treatment. Radiologic examination of the 2 cases showed bilateral urolithiasis probably caused by the high urinary urate excretion. Sequence analysis of a urate anion exchanger known to regulate blood urate level (URAT1 gene) in both brothers showed homozygous mutation in exon 4 (W258Stop), resulting in a premature truncated URAT1 protein. Both their parents and their children showed heterozygous mutation of the URAT1 gene. This is the first report of the 2 male siblings of familial renal hypouricemia complicated with exercise-induced ARF, with definite demonstration of genetic abnormality in the responsible gene (URAT1).

Acute Kidney Injury↗
PubMed1999

A presynaptic role for the ADP ribosylation factor (ARF)-specific GDP/GTP exchange factor msec7-1.

ADP ribosylation factors (ARFs) represent a family of small monomeric G proteins that switch from an inactive, GDP-bound state to an active, GTP-bound state. One member of this family, ARF6, translocates on activation from intracellular compartments to the plasma membrane and has been implicated in regulated exocytosis in neuroendocrine cells. Because GDP release in vivo is rather slow, ARF activation is facilitated by specific guanine nucleotide exchange factors like cytohesin-1 or ARNO. Here we show that msec7-1, a rat homologue of cytohesin-1, translocates ARF6 to the plasma membrane in living cells. Overexpression of msec7-1 leads to an increase in basal synaptic transmission at the Xenopus neuromuscular junction. msec7-1-containing synapses have a 5-fold higher frequency of spontaneous synaptic currents than control synapses. On stimulation, the amplitudes of the resulting evoked postsynaptic currents of msec7-1-overexpressing neurons are increased as well. However, further stimulation leads to a decline in amplitudes approaching the values of control synapses. This transient effect on amplitude is strongly reduced on overexpression of msec7-1E157K, a mutant incapable of translocating ARFs. Our results provide evidence that small G proteins of the ARF family and activating factors like msec7-1 play an important role in synaptic transmission, most likely by making more vesicles available for fusion at the plasma membrane.

ADP-Ribosylation Factors↗
PubMed1999

The ARF-like 2 (ARL2)-binding protein, BART. Purification, cloning, and initial characterization.

ARF-like proteins (ARLs) comprise a functionally distinct group of incompletely characterized members in the ARF family of RAS-related GTPases. We took advantage of the GTP binding characteristics of human ARL2 to develop a specific, high affinity binding assay that allowed the purification of a novel ARL2-binding protein. A 19-kDa protein (BART, Binder of Arl Two) was identified and purified from bovine brain homogenate. BART binding is specific to ARL2.GTP with high affinity but does not interact with ARL2.GDP or activated ARF or RHO proteins. Based on peptide sequences of purified bovine BART, the human cDNA sequence was determined. The 489-base pair BART open reading frame encodes a novel 163-amino acid protein with a predicted molecular mass of 18,822 Da. Recombinant BART was found to bind ARL2.GTP in a manner indistinguishable from native BART. Northern and Western analyses indicated BART is expressed in all tissues sampled. The lack of detectable membrane association of ARL2 or BART upon activation of ARL2 is suggestive of actions quite distinct from those of the ARFs. The lack of ARL2 GTPase-activating protein activity in BART led us to conclude that the specific interaction with ARL2.GTP is most consistent with BART being the first identified ARL2-specific effector.

Amino Acid Sequence↗
PubMed2005

Mislocalization or reduced expression of Arf GTPase-activating protein ASAP1 inhibits cell spreading and migration by influencing Arf1 GTPase cycling.

ADP-ribosylation factor (Arf) family of small GTP-binding proteins plays a central role in membrane trafficking and cytoskeletal remodeling. ASAP1 (Arf-GAP containing SH3, ankyrin repeats, and PH domain) is a phospholipid-dependent Arf GTPase-activating protein (Arf-GAP) that binds to protein-tyrosine kinases Src and focal adhesion kinase. Using affinity chromatography and mass spectrometry (MS), we identified the adaptor protein CD2-associated protein (CD2AP) as a candidate binding partner of ASAP1. Both co-immunoprecipitation and GST pull-down experiments confirmed that CD2AP stably interacts with ASAP1 through its N-terminal SH3 domains. Using a mislocalization strategy, we show that sequestration of endogenous ASAP1 to mitochondria with a CD2AP SH3-mito fusion protein (the three N-terminal SH3 domains of CD2AP fused to Listeria monocytogenes ActA mitochondria-targeting sequence) inhibited REF52 cell spreading and migration in response to fibronectin stimulation. Using an alternative strategy we show that suppressing ASAP1 expression with small interfering RNA duplexes also significantly retarded cell spreading and inhibited cell migration. Furthermore, abrogation of ASAP1 function using either small interfering RNAs or mislocalization approaches caused an increase of GTP loading on Arf1 and loss of paxillin from adhesions. These results taken together with our previous observations that overexpression of ASAP1 inhibits cell spreading and alters paxillin localization to adhesions (Liu, Y., Loijens, J. C., Martin, K. H., Karginov, A. V., and Parsons, J. T. (2002) Mol. Biol. Cell. 13, 2147-2156) suggest that the recruitment of certain adhesion components such as paxillin requires dynamic GTP/GDP turnover of Arf1 GTPase.

ADP-Ribosylation Factor 1↗
PubMed2003

Sequence, genomic organization, and expression of the human ADP-ribosylation factor 6 (ARF6) gene: a class III ARF.

ADP-ribosylation factor 6 (ARF6) is a member of a family of ~20-kDa guanine nucleotide-binding proteins that has been implicated to function in membrane ruffling and cell motility, endocytosis, exocytosis, and membrane recycling. Sequence analysis of the human ARF6 gene indicates it spans 4004 bp, contains a single 98-bp intron within the 5'-untranslated region, and is localized to chromosome 14q21. Similar to the class II ARF transcripts, translation of the ARF6 mRNA initiates in the second exon. Primer extension assays indicate that the major transcription initiation site is located 591 bp 5' to the start of translation, yielding the largest 5'-untranslated region of the known human ARFs. The proximal 5'-flanking region of the human ARF6 gene lacks a TATA box and is highly GC rich. Consistent with this promoter structure, expression analysis of a blot containing 50 human RNAs hybridized with an ARF6-specific oligonucleotide probe revealed that the ARF6 gene is expressed in all tissues; although higher levels of expression were observed in heart, substantia nigra, and kidney. A comparison of the genomic organization of the ARF genes reveals that the ARF6 gene (class III) structure is quite distinct from the class I (ARF1, ARF2, and ARF3) and class II (ARF4 and ARF5) ARF genes.

ADP-Ribosylation Factor 6↗
PubMed1999

Morphological changes of rat mandibular bone with ArF excimer laser in vivo.

OBJECTIVE: The purpose of this study was to investigate the morphological changes of bone tissue by ArF excimer laser irradiation in vivo. SUMMARY BACKGROUND DATA: Recently, it has been demonstrated that soft and hard tissues can be removed by excimer laser irradiation with little thermal damage. METHODS: ArF excimer laser was irradiated on the surface of the rat mandibular bone using the following parameters: wavelength; 193 nm; output: 0.12 W; pulse repetition rate: 10 Hz; spot size: 1.0 x 4.0 mm; irradiation time: 90 and 120 seconds. The ablation depth was measured at 90 and 120 seconds. Furthermore, the irradiated surface was examined histologically using scanning electron microscopy (SEM). RESULTS: The relationship between ablation depth and irradiation time was almost linear. Macroscopically, the ArF excimer laser beam produced a defect with clean-cut margins without carbonization in the mandibular bone. Histologically, there was minimal evidence of thermal damage to the surrounding tissue. The bottom of the defect revealed a sawtooth appearance. In SEM observation, mosaic structures corresponded to the sawtooth structures observed with light microscopy. CONCLUSIONS: These findings suggest that it is possible to remove bone tissue using ArF excimer laser irradiation without thermal damage. The effectiveness of this laser can be attributed to the photoablation of the bone tissue.

Animals↗
PubMed2002

Genetic status of cell cycle regulators in squamous cell carcinoma of the oesophagus: the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes are major targets for inactivation.

We determined inactivation of the CDKN2A (p16(INK4a) and p14(ARF)) gene in 21 cases of oesophageal squamous cell carcinoma (OSCC). The tumours were also analysed for mutations in exons 5-8 and allelic losses in the p53 gene. In addition, we screened the CDKN2B (p15 INK4b), CDKN2C (p18 INK4c), CDK4 and p53R2 genes for mutations in the tumour tissues. Besides concomitant alterations in the CDKN2A and p53 loci in more than half of the cases, our results showed that in 18 OSCC (86%) the CDKN2A (p16(INK4a) and p14(ARF) ) gene was affected through mutations, homozygous/hemizygous deletions and promoter hypermethylation. Eight out of 10 tumours with mutations or promoter hypermethylation specific to the CDKN2A/p16 INK4a gene showed loss of the wild-type allele. One tumour with a single base deletion in the N-terminus (codon 8) of the CDKN2A/p16(INK4a) gene carried a novel germ-line mutation or a rare polymorphism (Ile51Met) in exon 2 of the CDK4 gene. Promoter hypermethylation in the CDKN2A/p14 ARF gene was detected in 11 tumours. In the p53 gene 15 mutations were detected in 14 tumours. We detected an inverse relationship between CDKN2A/p16 INK4a inactivation and frequency of loss of heterozygosity at the p53 locus (OR 0.09, 95% CI 0.01-0.98; Fisher exact test, P-value approximately 0.03). Screening of nine exons of the p53R2 [Human Genome Organisation (HUGO) official name RRM2B] gene resulted in identification of a novel polymorphism in the 5' untranslated region, which was detected in four cases. Our results suggest that the CDKN2A (p16(INK4a) and p14(ARF) ) and p53 genes involved in the two cell cycle pathways are major and independent targets of inactivation in OSCC.

5' Untranslated Regions↗
PubMed2002

Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a structural device for 'front-back' communication.

Arf proteins are important regulators of cellular traffic and the founding members of an expanding family of homologous proteins and genomic sequences. They depart from other small GTP-binding proteins by a unique structural device, which we call the 'interswitch toggle', that implements front-back communication from the N-terminus to the nucleotide binding site. Here we define the sequence and structural determinants that propagate information across the protein and identify them in all of the Arf family proteins other than Arl6 and Arl4/Arl7. The positions of these determinants lead us to propose that Arf family members with the interswitch toggle device are activated by a bipartite mechanism acting on opposite sides of the protein. The presence of this communication device might provide a more useful basis for unifying Arf homologs as a family than do the cellular functions of these proteins, which are mostly unrelated. We review available genomic sequences and functional data from this perspective, and identify a novel subfamily that we call Arl8.

ADP-Ribosylation Factor 6↗
PubMed2004

Guanine nucleotide-exchange factors for arf GTPases: their diverse functions in membrane traffic.

Small GTPases of the Arf family, by cycling between GDP-bound inactive and GTP-bound active states, play a crucial role not only in the regulation of membrane traffic and dynamics but also in rearrangement of actin cytoskeleton. The exchange of GDP for GTP on Arf is catalyzed by a family of guanine nucleotide-exchange factors (GEFs) containing a Sec7 domain. The Sec7 domain is a target of brefeldin A, which inhibits various trafficking processes and induces organelle disintegration. During the past few years, significant progress has been made in elucidating the structure and catalytic mechanism of the Sec7 domains and physiological functions of the Sec7 domain-containing Arf-GEFs. Here we review the structures and functions of Arf-GEFs by focusing on the regulation of membrane traffic.

ADP-Ribosylation Factors↗
PubMed2004

Contrasting modes of diversification in the Aux/IAA and ARF gene families.

The complete genomic sequence for Arabidopsis provides the opportunity to combine phylogenetic and genomic approaches to study the evolution of gene families in plants. The Aux/IAA and ARF gene families, consisting of 29 and 23 loci in Arabidopsis, respectively, encode proteins that interact to mediate auxin responses and regulate various aspects of plant morphological development. We developed scenarios for the genomic proliferation of the Aux/IAA and ARF families by combining phylogenetic analysis with information on the relationship between each locus and the previously identified duplicated genomic segments in Arabidopsis. This analysis shows that both gene families date back at least to the origin of land plants and that the major Aux/IAA and ARF lineages originated before the monocot-eudicot divergence. We found that the extant Aux/IAA loci arose primarily through segmental duplication events, in sharp contrast to the ARF family and to the general pattern of gene family proliferation in Arabidopsis. Possible explanations for the unusual mode of Aux/IAA duplication include evolutionary constraints imposed by complex interactions among proteins and pathways, or the presence of long-distance cis-regulatory sequences. The antiquity of the two gene families and the unusual mode of Aux/IAA diversification have a number of potential implications for understanding both the functional and evolutionary roles of these genes.

Arabidopsis↗
PubMed1998

ASAP1, a phospholipid-dependent arf GTPase-activating protein that associates with and is phosphorylated by Src.

Membrane trafficking is regulated in part by small GTP-binding proteins of the ADP-ribosylation factor (Arf) family. Arf function depends on the controlled exchange and hydrolysis of GTP. We have purified and cloned two variants of a 130-kDa phosphatidylinositol 4, 5-biphosphate (PIP2)-dependent Arf1 GTPase-activating protein (GAP), which we call ASAP1a and ASAP1b. Both contain a pleckstrin homology (PH) domain, a zinc finger similar to that found in another Arf GAP, three ankyrin (ANK) repeats, a proline-rich region with alternative splicing and SH3 binding motifs, eight repeats of the sequence E/DLPPKP, and an SH3 domain. Together, the PH, zinc finger, and ANK repeat regions possess PIP2-dependent GAP activity on Arf1 and Arf5, less activity on Arf6, and no detectable activity on Arl2 in vitro. The cDNA for ASAP1 was independently identified in a screen for proteins that interact with the SH3 domain of the tyrosine kinase Src. ASAP1 associates in vitro with the SH3 domains of Src family members and with the Crk adapter protein. ASAP1 coprecipitates with Src from cell lysates and is phosphorylated on tyrosine residues in cells expressing activated Src. Both coimmunoprecipitation and tyrosine phosphorylation depend on the same proline-rich class II Src SH3 binding site required for in vitro association. By directly interacting with both Arfs and tyrosine kinases involved in regulating cell growth and cytoskeletal organization, ASAP1 could coordinate membrane remodeling events with these processes.

ADP-Ribosylation Factor 1↗
PubMed2005

Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF.

Recently, we demonstrated that peroxisome proliferator-activated receptor-alpha (PPARalpha) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990-F998, 2004). In the following studies, we examined the protective effect of PPARalpha ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-alpha, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARalpha ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARalpha ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARalpha null mice. In addition, we observed that cisplatin-induced NF-kappaB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARalpha ligand. These results demonstrate that PPARalpha exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-kappaB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.

Acute Kidney Injury↗