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PubMed1997

Cytohesin-1, a cytosolic guanine nucleotide-exchange protein for ADP-ribosylation factor.

Cytohesin-1, a protein abundant in cells of the immune system, has been proposed to be a human homolog of the Saccharomyces cerevisiae Sec7 gene product, which is crucial in protein transport. More recently, the same protein has been reported to be a regulatory factor for the alphaLbeta2 integrin in lymphocytes. Overexpression of human or yeast ADP-ribosylation factor (ARF) genes rescues yeast with Sec7 defects, restoring secretory pathway function. ARFs, 20-kDa guanine nucleotide-binding proteins initially identified by their ability to stimulate cholera toxin ADP-ribosyltransferase activity and now recognized as critical components in intracellular vesicular transport, exist in an inactive cytosolic form with GDP bound (ARF-GDP). Interaction with a guanine nucleotide-exchange protein (GEP) accelerates exchange of GDP for GTP, producing the active ARF-GTP. Both soluble and particulate GEPs have been described. To define better the interaction between ARF and Sec7-related proteins, effects of cytohesin-1, synthesized in Escherichia coli, on ARF activity were evaluated. Cytohesin-1 enhanced binding of 35S-labeled guanosine 5'-[gamma-thio]triphosphate [35S]GTP[gammaS] or [3H]GDP to ARF purified from bovine brain (i.e., it appeared to function as an ARF-GEP). Addition of cytohesin-1 to ARF3 with [35S]GTP[gammaS] bound, accelerated [35S]GTP[gammaS] release to a similar degree in the presence of unlabeled GDP or GTP[gammaS] and to a lesser degree with GDP[betaS]; release was negligible without added nucleotide. Cytohesin-1 also increased ARF1 binding to a Golgi fraction, but its effect was not inhibited by brefeldin A (BFA), a drug that reversibly inhibits Golgi function. In this regard, it differs from a recently reported BFA-sensitive ARF-GEP that contains a Sec7 domain.

ADP-Ribosylation Factor 1↗
PubMed1995

Cytosolic ADP-ribosylation factors are not required for endosome-endosome fusion but are necessary for GTP gamma S inhibition of fusion.

A specific role for ADP-ribosylation factors (ARFs) in in vitro endosome-endosome fusion has been proposed (Lenhard, J. M., Kahn, R. A., and Stahl, P. D. (1992) J. Biol. Chem. 267, 13047-13052). However, in vivo studies have failed to support a function for ARFs in the endocytic pathway, since an antagonist of ARF activities, brefeldin A, does not interfere with receptor internalization (Schonhorn, J. E., and Wessling-Resnick, M. (1994) Mol. Cell. Biochem. 135, 159-164). This controversy surrounding the exact function of ARF in endocytic vesicle traffic prompted us to critically re-examine the involvement of ARFs in cell-free endosome fusion. Cytosol depleted of ARF activity was capable of supporting in vitro endocytic vesicle fusion but failed to support inhibition of this reaction in the presence of guanosine 5'-3-O-(thio)triphosphate (GTP gamma S). Addition of purified ARF1 restored the ability of the ARF-depleted cytosol to inhibit endosome fusion when incubated with GTP gamma S. Both endocytic vesicle fusion and the GTP gamma S-mediated inhibition of vesicle fusion were unaffected by brefeldin A. Moreover, the ATP requirement and kinetics of cell-free fusion are not altered by brefeldin A or depletion of cytosolic ARFs. These results suggest that cytosolic ARFs are not necessary for endosomal vesicle fusion in vitro but are responsible for inhibition of fusion in the presence of GTP gamma S and cytosolic factors in a brefeldin A-resistant manner.

ADP-Ribosylation Factor 1↗
PubMed1997

Characterization of a GDP dissociation inhibitory region of ADP-ribosylation factor domain protein ARD1.

ADP-ribosylation factors (ARFs) are approximately 20-kDa guanine nucleotide-binding proteins initially identified by their ability to stimulate cholera toxin ADP-ribosyltransferase activity and later recognized as critical components in intracellular vesicular transport and phospholipase D activation. ARF domain protein 1 (ARD1) is a member of the ARF family that differs from other ARFs by the presence of a 46-kDa amino-terminal extension. We previously reported that this extension acts as a GTPase-activating protein for the ARF domain of ARD1 (Vitale, N., Moss, J., and Vaughan, M. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 1941-1944). Both GTP binding and GTP hydrolysis are necessary for physiological function of guanine nucleotide-binding proteins, and the rates of GDP/GTP exchange and GTPase activity are critical in the activation/deactivation cycle. Dissociation of GDP from the ARF domain of ARD1 was faster than from ARD1 itself (both proteins synthesized in Escherichia coli). Using deletion mutations, it was demonstrated that the 15 amino acids directly preceding the ARF domain were responsible for decreasing the rate of GDP dissociation but not guanosine 5-[gamma-thio]triphosphate dissociation. By site-specific mutagenesis it was shown that hydrophobic amino acids in this region were particularly important in stabilizing the GDP-bound form of ARD1. It is suggested that, like the amino-terminal segment of ARF, the equivalent region in ARD1, located between the GTPase-activating protein and ARF domains, may act as a GDP dissociation inhibitor.

ADP-Ribosylation Factors↗
PubMed1998

Effects of arfaptin 1 on guanine nucleotide-dependent activation of phospholipase D and cholera toxin by ADP-ribosylation factor.

Arfaptin 1, a approximately 39-kDa protein based on the deduced amino acid sequence, had been initially identified in a yeast two-hybrid screen using dominant active ARF3 (Q71L) as bait with an HL-60 cDNA library. It was suggested that arfaptin 1 may be involved in Golgi functions, since the FLAG-tagged protein was associated with Golgi membranes when expressed in COS-7 cells and could be bound to Golgi in vitro in an ADP-ribosylation factor (ARF)- and GTPgammaS-dependent, brefeldin A-inhibited fashion. Arfaptin 2, found in the same two-hybrid screen as arfaptin 1, is 60% identical in amino acid sequence and may or may not have an analogous function. We now report some effects of arfaptin 1 on ARF activation of phospholipase D and cholera toxin ADP-ribosyltransferase. Arfaptin 1 inhibited activation of both enzymes in a concentration-dependent manner and was without effect in the absence of ARF. Two ARF1 mutants that activated the toxin, one lacking 13 N-terminal amino acids and the other, in which 73 residues at the N terminus were replaced with the analogous sequence from ARL1, were not inhibited by arfaptin, consistent with the conclusion that arfaptin interaction requires the N terminus of ARF. This region has also been implicated in phospholipase D activation, but whether the two proteins interact with the same structural elements in ARF remains to be determined. Arfaptin inhibition of the action of ARF5 and ARF6 was less than that of ARF1 and ARF3; its effects were less on nonmyristoylated than myristoylated ARFs. Arfaptin effects on guanine nucleotide binding by ARFs were minimal whether or not a purified ARF guanine nucleotide-exchange protein was present. These findings indicate that arfaptin acts as an inhibitor of ARF actions in vitro, raising the possibility that it has a similar role in vivo.

ADP-Ribosylation Factor 1↗
PubMed2002

CARF is a novel protein that cooperates with mouse p19ARF (human p14ARF) in activating p53.

The INK4a locus on chromosome 9p21 encodes two structurally distinct tumor suppressor proteins, p16(INK4a) and the alternative reading frame protein, ARF (p19(ARF) in mouse and p14(ARF) in human). Each of these proteins has a role in senescence of primary cells and activates pathways for cell cycle control and tumor suppression. The current prevailing model proposes that p19(ARF) activates p53 function by antagonizing its degradation by MDM2. It was, however, recently shown that stabilization of p53 by p14(ARF) occurs independent of the relocalization of MDM2 to the nucleolus. We have identified a novel collaborator of ARF, CARF. It co-localizes and interacts with ARF in the nucleolus. We demonstrate that CARF is co-regulated with ARF, cooperates with it in activating p53, and thus acts as a novel component of the ARF-p53-p21 pathway.

3T3 Cells↗
PubMed2003

p19Arf-p53 tumor suppressor pathway regulates cell motility by suppression of phosphoinositide 3-kinase and Rac1 GTPase activities.

The p19(Arf)-p53 tumor suppressor pathway plays a critical role in cell-cycle checkpoint control and apoptosis, whereas Rho family small GTPases are key regulators of actin structure and cell motility. By using primary mouse embryonic fibroblasts that lack Arf, p53, or both, we studied the involvement of the p19(Arf)-p53 pathway in the regulation of cell motility and its relationship with Rho GTPases. Deletion of Arf and/or p53 led to actin cytoskeleton reorganization and a significant increase in cell motility. The endogenous phosphoinositide (PI) 3- kinase and Rac1 activities were elevated in Arf(-/-) and p53(-/-) cells, and these activities are required for p19(Arf)- and p53-regulated migration. Reintroduction of the wild type Arf or p53 genes into Arf(-/-) or p53(-/-) cells reversed the PI 3-kinase and Rho GTPase activities as well as the migration phenotype. These results suggest a functional relationship between an established tumor suppressor pathway and a signaling module that controls actin structure and cell motility and show that p19(Arf) and p53 negatively regulate cell migration by suppression of PI 3-kinase and Rac1 activities.

Animals↗
PubMed2004

Retracted: p14ARF induces G2 cell cycle arrest in p53- and p21-deficient cells by down-regulating p34cdc2 kinase activity.

The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF). Although primarily proposed to require a functional p53.Mdm-2 signaling axis, recently p14(ARF) has been implicated in p53-independent cell cycle regulation. Here we show that p14(ARF) preferentially induces a G(2) arrest in tumor cells lacking functional p53 and/or p21. Expression of p14(ARF) impaired mitotic entry and enforced a primarily cytoplasmic localization of p34(cdc2) that was associated with a decrease in p34(cdc2) kinase activity and reduced p34(cdc2) protein expression. A direct physical interaction between p14(ARF) and p34(cdc2) was, nevertheless, ruled out by lack of co-immunoprecipitation. The p14(ARF)-induced depletion of p34(cdc2) was associated with impaired cdc25C phosphatase expression and a prominent shift to inhibitory Tyr-15-phosphorylation in G(2)-arrested cells lacking either p53, p21, or both. Finally, reconstitution of p34(cdc2) using a constitutively active, phosphorylation-deficient p34(cdc2AF) mutant alleviated this p14(ARF)-induced G(2) arrest, thereby allowing cell cycle progression. Taken together, these data indicate that p14(ARF) arrests cells lacking functional p53/p21 in the G(2) phase of the cell cycle by targeting p34(cdc2) kinase. This may represent an important fail-safe mechanism by which p14(ARF) protects p53/p21-deficient cells from unrestrained proliferation.

CDC2 Protein Kinase↗
PubMed2004

Causes and prognosis of nontraumatic acute renal failure requiring dialysis in adult patients with and without diabetes.

Despite advanced techniques of renal replacement therapy the overall mortality of patients with ARF is still high. The majority of patients with ARF requiring dialysis are those with nontraumatic ARF. In a retrospective study we compared the causes of nontraumatic ARF, the risk factors for the development of renal failure and the mortality rates in patients with and without diabetes mellitus who received dialysis therapy in the years 1991-2000. A total of 232 patients were included in the study, 34 (14.6%) of them with and 198 patients (85.4%) without diabetes. The predominant causes of nontraumatic ARF like congestive heart failure (26.4 vs. 13.6, p < 0.05) and hypotension/hypovolemia (20.6 vs. 7.6%, p < 0.05) occurred more frequently in diabetic patients. The prevalence of sepsis (8.8 vs. 10.1%, NS), malignancy/ hypercalcemia (5.8 vs. 11.6%, NS) and other causes of nontraumatic ARF were similar in both groups. The prevalence of hepato-renal syndrome (5.8 vs. 13.6%, p < 0.05) and acute kidney graft failure (2.9 vs. 15.1%, p < 0.05) was higher in the nondiabetic individuals. Patients with diabetes showed more often chronic predictors for the onset of ARF like pre-existing hypertension (93.6 vs. 51.0%, p < 0.05), congestive heart failure (44.1 vs. 14.6%, p < 0.005), pre-existing renal insufficiency (76.4 vs. 46.9%, p < 0.05) and ACE-inhibitor therapy (32.3 vs. 9.6%, p < 0.005). Additionally, the prevalence of multiple organ failure (MOF) as prognostic factor was significantly higher in the diabetic patients (47.0 vs. 21.7%, p < 0.05). The mean number of dialyses therapy was 4.7 vs. 4.5 per patient. The overall mortality was 41.1 vs. 44.% (NS). In conclusion, the prevalence of the most common causes of nontraumatic ARF was different between the patients with and without diabetes. The diabetic individuals had more frequently predictors for the onset of ARF. The overall mortality was approximately the same in both groups.

Acute Kidney Injury↗
PubMed2003

Prediction of acute renal failure after cardiac surgery: retrospective cross-validation of a clinical algorithm.

BACKGROUND: Acute renal failure (ARF) after cardiac surgery is associated with high costs and a poor prognosis. Based on the results of a large US study, an algorithm has been developed for predicting ARF from pre-operative risk factors. The aim of this study was to cross-validate this algorithm in a patient population from Europe, and to assess its usefulness as a clinical tool. METHODS: All coronary bypass and valvular surgery patients from a 5-year period were included. Data on pre-operative risk factors for all patients who developed dialysis-dependent ARF and for a random sample of patients without ARF were retrospectively obtained from hospital databases and medical records. For each patient, a risk score for ARF was calculated on the basis of the algorithm. The sensitivity, specificity, positive and negative predictive values and area under receiver operating characteristic (ROC) curve of the score's ability to predict ARF were estimated. RESULTS: 2037 patients were included. The risk of ARF was 1.9%, and the area under the ROC curve 0.71. For a risk score of 6 or higher, the sensitivity was 0.53, the specificity 0.71, the positive predictive value 0.03 and the negative predictive value 0.99. CONCLUSIONS: The validity of the algorithm was confirmed in a population differing in several aspects from the US populations where it was developed. Although it is useful for estimating the risk of ARF in groups of patients, the low risk of ARF limits the algorithm's ability to predict the outcome for individual patients.

Acute Kidney Injury↗
PubMed1984

Role of serotonin in patients with acute respiratory failure.

An early event in the evolution of acute respiratory failure (ARF) is thought to be the activation of platelets, their pulmonary entrapment and subsequent release of the smooth muscle constrictor serotonin (5HT). This study tests the thesis that inhibition of 5HT will improve lung function. The etiology of ARF in the 18 study patients was sepsis (N = 10), aspiration (N = 3), pancreatitis (N = 1), embolism (N = 2), and abdominal aortic aneurysm surgery (N = 2). Patients were divided into two groups determined by whether their period of endotracheal intubation was less than or equal to 4 days (early ARF, N = 12) or greater than 4 days (late ARF, N = 6). Transpulmonary platelet counts in the early group showed entrapment of 26,300 +/- 5900 platelets/mm3 in contrast to the late group where there was no entrapment (p less than 0.05). The platelet 5HT levels in the early group were 55 +/- 5 ng/10(9) platelets, values lower than 95 +/- 15 ng/10(9) platelets in the late ARF group (p less than 0.05), and 290 +/- 70 ng/10(9) platelets in normals. The selective 5HT receptor antagonist, ketanserin was given as an intravenous bolus over 3 minutes in a dose of 0.1 mg/kg, followed by a 30-minute infusion of 0.08 mg/kg. During this period mean arterial pressure (MAP) fell from 87 +/- 5 to 74 +/- 6 mmHg (mean +/- SEM) (p less than 0.05). One and one-half hours following the start of therapy, MAP returned to baseline. At this time, patients with early ARF showed decreases in: physiologic shunt (Qs/QT) from 26 +/- 3 to 19 +/- 3 (p less than 0.05); peak inspiratory pressure from 35 +/- 2 to 32 +/- 2 cmH2O (p less than 0.05) and in mean pulmonary arterial pressure from 32 +/- 2 to 29 +/- 1 mmHg (p less than 0.05). At 4 hours all changes returned to baseline levels. In early ARF ketanserin did not alter pretreatment values of: pulmonary arterial wedge pressure, 17 +/- 3 mmHg; cardiac index, 2.8 +/- 0.3 L/min X m2; platelet count, 219,000 +/- 45,000/mm3; platelet 5HT, 55 +/- 5 ng/10(9) platelets; plasma 5HT, 142 +/- 21 ng/ml; plasma thromboxane B2, 190 +/- 30 pg/ml; or plasma 6-keto-PGF1 alpha, 40 +/- 10 pg/ml. Ketanserin infusion in patients with late ARF yielded no benefit. In both ARF groups the decreases in QS/QT were inversely related to the duration of intubation (r = 0.70; p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed2004

Acute renal failure after nonmyeloablative hematopoietic cell transplantation.

Acute renal failure (ARF) is a common life-threatening complication after myeloablative allogeneic hematopoietic cell transplantation (HCT). Nonmyeloablative HCT aims to eradicate the malignancy with graft-versus-tumor effect, rather than with high doses of chemoradiotherapy. It may be anticipated that a lower risk of ARF exists in nonmyeloablative HCT as a result of the milder preconditioning regimen. However, the patients who receive the nonmyeloablative HCT are older individuals who are not eligible for the more toxic allogeneic myeloablative procedure. The goal of this study was to evaluate ARF in a large group of patients who received nonmyeloablative HCT. This cohort study enrolled patients who were undergoing nonmyeloablative HCT at four major centers from 1998 to 2001. Conditioning therapy involved total body irradiation 2 Gy +/- fludarabine 30 mg/m2. Posttransplantation immunosuppression consisted of cyclosporine or tacrolimus and mycophenolate mofetil. ARF was classified into four grades, similar to previous studies in the literature. Collectively, 253 patients were recruited into this study. ARF (>50% decrease in GFR) occurred in 40.4% of patients over a 3-mo period, with 4.4% of patients requiring dialysis. The overall mortality in the study population was 34% at 1 yr. The mortality increased with worsening grade of ARF. The combined need for dialysis and artificial ventilation was associated with a mortality exceeding 80%. Although the number of patients who develop ARF is significant, the risk of developing ARF that requires dialysis after nonmyeloablative HCT is infrequent despite the older age of the patients. The data are also suggestive that ARF may contribute to mortality after nonmyeloablative HCT.

Acute Kidney Injury↗
PubMed2006

Successful transplantation of kidneys from deceased donors with acute renal failure: Three-year results.

BACKGROUND: Kidneys from deceased donors with acute renal failure (ARF) are generally not accepted for transplantation because of the expected poor outcome. This prospective study examined the utilization of kidneys from donors with ARF for transplantation and the outcomes. METHODS: Fifty-five kidneys from donors with ARF were transplanted. The outcome was compared with concurrent and matched 55 recipients of standard criteria donor (SCD) kidneys and 55 expanded criteria donor (ECD) kidneys. ARF kidneys were accepted from donors aged <50 years, a negative history for kidney disease, and a negative pretransplant biopsy for chronic structural changes. The immunosuppression was similar in all three groups. The outcome measurements included three-year patient and graft survival, biopsy-proven acute rejection (BPAR), subclinical acute rejection (SCAR), and chronic allograft nephropathy (CAN), serum creatinine, and creatinine clearance. RESULTS: Three-year patient and graft survival was 90% and 90% in ARF group, 100% and 89% in SCD group and 83% and 66% in ECD group. BPAR and SCAR were comparable in the groups but CAN was significantly higher in ECD group. Mean serum creatinine levels were 1.9+/-1.1, 1.9+/-0.9, and 2.2+/-1.3 mg/dl and mean creatinine clearances were 66+/-15, 68+/-14, and 58+/-10 mls/minute in ARF, SCD, and ECD groups, respectively (SCD and ARF vs. ECD P = 0.04). CONCLUSIONS: Transplantation of kidneys from selected deceased donors with ARF provides comparable survival and function compared to kidneys from non-ARF donors and may be considered for transplantation to expand the donor pool to overcome the current acute shortage of kidneys.

Acute Kidney Injury↗
PubMed2006

Incidence and risk factors for the development of acute renal failure in patients with ventilator-associated pneumonia.

AIM: Infections are one of the most important risk factors for the development of acute renal failure (ARF) and ventilator-associated pneumonia (VAP) has been reported as one of the most frequent infection in intensive care units (ICU). Sepsis, shock, multiorgan dysfunction syndrome (MODS), use of nephrotoxic antibiotics and mechanical ventilation are potential risk factors for development of ARF during VAP. The objective of the study was to evaluate the incidence of ARF in patients with VAP and the role of VAP-related potential risk factors in the development of ARF. METHODS: One hundred and eight patients who were admitted to the pulmonary ICU of a university hospital and developed VAP were included in this prospective observational cohort study. Only first episodes of VAP were studied. Diagnosis was based on microbiologically confirmed clinical findings. Potential outcome variables including responsible pathogens, recurrence, polymicrobial aetiology, bacteraemia, multidrug resistance of microorganisms, late/early VAP and sepsis and other known risk factors for development of ARF were evaluated. Risk factors were analysed by logistic regression analysis for significance. RESULTS: Incidence of ARF was 38% (n = 41). Pneumonia with multidrug resistant pathogens (odds ratio, (OR) 5; 95% confidence interval (95%CI), 1.5-18; P = 0.011), sepsis (OR, 5.6; 95%CI, 1.7-18; P = 0.005) and severity of admission disease (Acute Physiology and Chronic Health Evaluation II score: OR, 1.1; 95%CI, 1.02-1.3; P = 0.017) were independent risk factors for the development of ARF during VAP episodes in multivariate analysis. CONCLUSION: These results showed that the incidence of ARF is high during the VAP episodes and that VAP developed with multidrug resistant pathogens and sepsis have an independent effect on the development of ARF.

Acute Kidney Injury↗
PubMedDate not supplied

Dose of dialysis in acute renal failure.

Acute renal failure (ARF) is a cause of significant morbidity and mortality. Despite advances in supportive care, outcomes in ARF have improved little over the past decades. The primary goals in management of patients with ARF are to optimize hemodynamic and volume status, minimize further renal injury, correct metabolic abnormalities, and permit adequate nutrition. Renal replacement therapy (RRT) is often required to achieve these goals while awaiting renal recovery, but the optimal dose of dialysis in patients with ARF is not known. Extrapolation of required dialysis dose from recommendations in chronic dialysis is unlikely to be appropriate because of the lack of a steady state and differences in distribution volume of urea that are intrinsic to ARF. The prescribed dialysis dose in ARF is often low, and actual delivered dose is often even less than prescribed. Delivery of dialysis in ARF is often hampered by the patient's hypercatabolic state, hemodynamic instability, and volume status, as well as suboptimal vascular access with temporary venous catheters. The impact of intermittent hemodialysis (IHD) versus continuous renal replacement therapy (CRRT) on outcomes in ARF is also not clear. Patient disease severity impacts more than dialysis modality in patient outcome, but when patients are stratified for equal disease severity, CRRT may have potential benefits over IHD in terms of patient survival, fluid and metabolic control, and renal recovery. Strategies associated with improved outcomes that have emerged thus far in ARF are to aim for a time-averaged blood urea nitrogen (BUN) of less than 60 mg/dl with IHD, varying IHD frequency as necessary, or to achieve a minimum ultrafiltration rate of 35 ml/kg/hr with CRRT.

Acute Kidney Injury↗
PubMed1990

Incidence and prognosis of acute renal failure in older patients.

Few studies have assessed the prevalence and outcome of acute renal failure (ARF) in the elderly. Among 437 ARF cases prospectively studied during a nine-year period in a nephrology department, 152 (35%) occurred in patients over 70 years of age (Group 1). Patients over 70 account for only 10.5% of all hospital admissions in our country, and prevalence of ARF was 3.5 times higher in these patients than in younger people. Acute tubular necrosis (ATN) was diagnosed in 40% of Group 1 and 52% of the younger patients (Group 2) (P less than .05), whereas prerenal ARF was found in 47% and 32%, respectively (P less than .001). Dehydration was the most frequent cause of prerenal ARF in the elderly (51%). The etiological distribution of ATN was similar in both groups, being of multifactorial origin in most cases. Oliguria was present in 49% of ATN in Group 1 and in 66% of Group 2 (P less than .05). There were no significant differences in dialysis needs. Mortality was higher in the elderly in all types of ARF, although differences did not reach statistical significance. Need for dialysis, mechanical respiration, decreased level of consciousness, and hypotension were associated with poor prognosis in both groups. Total recovery from ARF in older persons was less frequent and slower than in younger patients. It may be concluded that patients over 70 years of age are at high risk for developing ARF; nevertheless, age should not be used as a discriminating factor in therapeutic decisions concerning ARF.

Acute Kidney Injury↗
PubMed2004

p14ARF expression increases dihydrofolate reductase degradation and paradoxically results in resistance to folate antagonists in cells with nonfunctional p53.

The p14(ARF) protein, the product of an alternate reading frame of the INK4A/ARF locus on human chromosome 9p21, disrupts the ability of MDM2 to target p53 for proteosomal degradation and causes an increase in steady-state p53 levels, leading to a G(1) and G(2) arrest of cells in the cell cycle. Although much is known about the function of p14(ARF) in the p53 pathway, not as much is known about its function in human tumor growth and chemosensitivity independently of up-regulation of p53 protein levels. To learn more about its effect on cellular proliferation and chemoresistance independent of p53 up-regulation, human HT-1080 fibrosarcoma cells null for p14(ARF) and harboring a defective p53 pathway were stably transfected with p14(ARF) cDNA under the tight control of a doxycycline-inducible promoter. Induction of p14(ARF) caused a decrease in cell proliferation rate and colony formation and a marked decrease in the level of dihydrofolate reductase (DHFR) protein. The effect of p14(ARF) on DHFR protein levels was specific, because thymidylate kinase and thymidylate synthase protein levels were not decreased nor were p53 or p21WAF1 protein levels increased. The decrease in DHFR protein was abolished when the cells were treated with the proteasome inhibitor MG132, demonstrating that p14(ARF) augments proteasomal degradation of the protein. Surprisingly, induction of p14(ARF) increased resistance to the folate antagonists methotrexate, trimetrexate, and raltitrexed. Depletion of thymidine in the medium reversed this resistance, indicating that p14(ARF) induction increases the reliance of these cells on thymidine salvage.

Cell Division↗
PubMed1990

Acute renal failure in man: new aspects concerning pathogenesis. A morphometric study.

The morphometric investigation of the proximal and distal tubules, the cortical interstitium, the intertubular capillaries, the renal corpuscles and the juxtaglomerular apparatuses (JGAs) in 56 cases in the oligoanuric, polyuric, and normuric phases of human acute renal failure (ARF), 6 cases of myeloma kidney with clinically confirmed ARF and 21 control kidneys revealed the following: (1) The main pathological change in human ARF is swelling of the epithelial cells of the proximal and distal tubules. Necrosis of these cells was observed in some cases but usually only as single cell necroses. (2) The interstitium of the cortex and of the outer stripe of the outer medulla is significantly widened in most cases of ARF. (3) In proximal tubules proximal to occluding casts (which were observed only in the plasmacytoma cases), the lumina are not widened but are narrower than normal, and the cross-sectional area of the epithelium is not greater but smaller than normal. (4) The JGAs were significantly larger in kidneys in the oligoanuric phase of ARF (with 1 exception) than in normal kidneys. In the normuric and polyuric phases they were slightly (not significantly) smaller than normal. In myeloma kidneys with occluding casts and/or diffuse interstitial fibrosis, the JGAs were significantly smaller than normal. From these findings it is concluded that: (1) The fall in glomerular filtration rate (GFR) in the postshock phase of ARF is not caused by nonselective back-diffusion of the primary urine through necrotic tubules or by compression of the lumina of the proximal and distal tubules by interstitial edema. A fall in GFR associated with occluding casts in the distal tubules is found only in the myeloma kidney and does not lead to widening of the proximal tubules but to tubular atrophy and narrowing of the lumen. (2) The casts seen in the lumina of the ascending limb of Henle's loop in some cases of ARF, which consist of hemoglobin, Tamm-Horsfall protein or desquamated blebs, do not occlude the lumen, since they are not associated with atrophy or luminal dilatation of the proximal tubules. (3) The JGAs with their secretory product renin-angiotensin II, together with adenosine, which is released in kidneys with ischemic or toxic damage, play a critical role in the pathogenesis of ARF. (4) In myeloma kidneys with ARF, in which the JGAs are markedly atrophic, the potentiated effect of adenosine that has been observed with a chronic absence of urine flow probably leads to a progressive, irreversible drop in GFR associated with tubular atrophy.

ADP-Ribosylation Factor 6↗
PubMed1995

Acute renal failure in patients following bone marrow transplantation: prevalence, risk factors and outcome.

To assess the prevalence, risk factors, clinical causes and outcome of acute renal failure (ARF) following bone marrow transplantation (BMT), a retrospective analysis of 275 patients was undertaken. ARF was diagnosed in 72 patients (26%) and occurred in 81.9% within the first month. The three main clinical causes were multifactorial (36%), nephrotoxic (29%), and veno-occlusive disease of the liver (VOD) 15%. The prevalence was higher in allogeneic BMT (36%) than in autologous BMT (6.5%). Risk factors related to the development of ARF wee preexisting VOD and age older than 25 years. Logistic regression in allogeneic BMT confirmed this association (VOD, odds ratio 3.8; age offer than 25, odds ratio 1.9). Underlying disease, graft-versus-host disease, sepsis, conditioning therapy, and sex were not associated with ARF. Seventeen cases of ARF required hemodialysis (24%) mainly in association with VOD (70.5%). The overall morality from ARF was 45.8%, the dialyzed group having the highest mortality (88%). Survival in the ARF group was continuously worse up to 3 months and the actuarial survival at 10 years was 29.7 versus 53.2%. We conclude that ARF is a common complication mainly in allogeneic BMT and carries a grave prognosis. VOD and age were risk factors for ARF.

Actuarial Analysis↗