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PubMed2003

Increased expression of CD54, CD18, MHC class II molecules, and proliferating cell nuclear antigen in acute puromycin aminonucleoside nephrosis.

Cellular infiltration to renal tissues is an important feature during acute puromycin aminonucleoside nephrosis (PAN) in rats. The mechanisms responsible for this infiltration are poorly understood. To elucidate the participation of adhesion molecules in PAN, nephrosis was induced in rats by intraperitoneal puromycin aminonucleoside injection. Controls represent animals injected with a 0.9% saline solution. ICAM-1 (intercellular adhesion molecule 1), CD18 (beta chain of lymphocyte-function-associated antigen), LCA (leukocyte common antigen), ED1 (monocyte/macrophage marker), and proliferating cell nuclear antigen expressions were evaluated in renal tissues 1, 2, and 7 weeks after injection. Frozen sections from PAN rat kidneys showed increased expressions of ICAM-1 and its ligand, and these findings were associated with increased levels of LCA+ and ED1+ cells in glomerulus and interstitium. The kinetics of leukocyte infiltration was similar to the kinetics of ICAM-1 expression: high values at week 2 which returned to normal values at week 7. Increased glomerular and interstitial proliferative activities (proliferating cell nulear antigen positive cells) were also found at week 2 of nephrosis. There was a correlation between ICAM-1 expression and numbers of LCA+ and ED1+ cells and between numbers of LCA+ cells and proliferating cells in glomerulus and interstitium. Correlations between glomerular and tubular ICAM-1 expression, interstitial leukocyte infiltration, and glomerular, interstitial, and tubular proliferative activities with the proteinuria were also observed during the nephrotic phase. In addition, increased lymphocyte binding to PAN renal tissues was observed, and this binding was diminished by anti-LFA-1beta monoclonal antibody pretreatment of lymphocytes. A similar result was found with anti-ICAM-1 monoclonal antibody pretreatment of renal tissues. Our results suggest that increased expression of ICAM-1 and proliferative activity could be important determinants in the renal hypercellularity found in this experimental model.

Acute Disease↗
PubMed1985

The effect of captopril on urinary protein excretion in puromycin aminonucleoside nephrosis in rats.

We investigated the effect of captopril, an orally active angiotensin converting enzyme inhibitor, on urinary protein excretion in puromycin aminonucleoside nephrotic rats. The administration of captopril (10 mg/100 g body weight) decreased proteinuria on days 10-14 following the administration of puromycin aminonucleoside (73.0 versus 125.0 mg, p less than 0.01), without affecting glomerular filtration rate. The beneficial effect of captopril was not abolished by the continuous intravenous infusion of angiotensin II (10 micrograms/kg/h for 9 days) or subcutaneous injections of aprotinin (50,000 KIU/day for 3 days). Indomethacin, in moderate (5 mg/kg/day for 3 days) or high (10 mg/kg/day) doses, abolished the captopril attenuation in urinary protein excretion. The salutory effect of captopril was characterized by a reduction in the fractional excretion of protein without compromising the glomerular filtration rate. No difference in renal ultrastructure was noted in captopril-treated versus control animals. Captopril was ineffective in reducing urinary protein excretion in rats with adriamycin-induced glomerulopathy. We conclude that captopril acts to reduce proteinuria in renal disease states arising from depletion of the glomerular basement membrane polyanion. The mechanism of action is postulated to be an alteration in renal hemodynamics, namely increased blood flow and a decrease in the ultrafiltration coefficient, that are the consequence of increased intrarenal prostaglandin production.

Angiotensins↗
PubMed2003

Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton.

Potent, specific, chemically stable and non-peptide/small-molecular inhibitors of puromycin-sensitive aminopeptidase, such as 3-(2,6-diethylphenyl)-2,4(1H,3H)-quinazolinedione (PAQ-22, 5), were prepared by the structural development of a potent PSA inhibitor, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22, 4). The design was carried out partly by applying electrostatic potential field information obtained from PIQ-22 (4) and its derivatives based on thalidomide (2). This information revealed that a positive electrostatic potential field around the benzylic methylene in the tetrahydroisoquinoline ring is necessary for potent activity. Lineweaver-Burk plot analysis showed that PAQ-22 (5) and its derivatives inhibit puromycin-sensitive aminopeptidase (PSA) in a non-competitive manner. These potent and specific PSA inhibitors showed dose-dependent cell invasion-inhibitory activity in a Matrigel assay using mouse melanoma B16F10/L5 cells, in spite of their low cell toxicity.

Aminopeptidases↗
PubMed1995

Dietary vitamin E supplementation ameliorates renal injury in chronic puromycin aminonucleoside nephropathy.

Chronic puromycin aminonucleoside nephropathy (PAN) is an experimental analog of focal segmental glomerulosclerosis. Progressive renal damage in this model is partly mediated by excessive production of oxidant species. Whether dietary supplementation with vitamin E, an endogenous lipophilic antioxidant, ameliorates the severity of chronic PAN was tested. PAN was induced by seven serial injections of the glomerular epithelial cell toxin puromycin aminonucleoside, 2 mg/100 g body wt per dose, over a 12-wk period. Experimental animals (N = 8) received vitamin E-enriched chow (100 IU/kg), whereas control PAN rats (N = 10) were fed standard rodent diet containing vitamin E (30 IU/kg of chow). The administration of vitamin E had no effect on somatic growth or blood pressure; however, rats with PAN fed the vitamin E-enriched diet had an increased hematocrit. In addition, the experimental diet resulted in a 50% reduction in urinary total protein and albumin excretion and stabilization of the serum albumin, cholesterol, and triglyceride concentrations (P < 0.01). The inulin clearance was 69% higher in the vitamin E-supplemented animals (P < 0.001). Tubular function, namely, phosphate reabsorption and beta 2-microglobulin excretion, was improved in rats with chronic PAN treated with the vitamin E-enriched diet. There was a significant decrease in glomerulosclerosis and glomerular planar area, and tubulointerstitial scarring was diminished in vitamin E-treated animals with chronic PAN (P < 0.01). These beneficial effects on renal structure and function were associated with reduced malondialdehyde content in the kidney and liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Puromycin induces apoptosis of developing chick sympathetic neurons in a similar manner to NGF-deprivation.

Survival of sympathetic neurons of chick embryo depends on nerve growth factor (NGF), and removal of NGF from culture medium caused apoptosis. We found that puromycin, an analogue of aminoacyl-tRNA, also induced apoptosis in a manner quite similar to that caused by NGF-deprivation. First, transcriptional inhibitors such as actinomycin D and alpha-amanitin effectively prevented both apoptoses, suggesting a requirement of gene expression. Second, the apoptoses were effectively prevented by translational inhibitors acting on peptidyltransfer reaction, such as anisomycin and blasticidin S. On the other hand, emetine, an inhibitor of translocation of peptidyl-tRNA, was not effective. Finally, NGF-deprivation and puromycin-addition affected the same three phosphorylated proteins to undergo dephosphorylation or to be eliminated. Besides, these changes were suppressed by anisomycin and blasticidin, but not by emetine. Based on these findings, we discuss the mechanism to induce apoptosis of chick sympathetic neurons.

Animals↗
PubMed1997

Kinetic study of irreversible inhibition of an enzyme consumed in the reaction it catalyses. Application to the inhibition of the puromycin reaction by spiramycin and hydroxylamine.

A systematic procedure for the kinetic study of irreversible inhibition when the enzyme is consumed in the reaction which it catalyses, has been developed and analysed. Whereas in most reactions the enzymes are regenerated after each catalytic event and serve as reusable transacting effectors, in the consumed enzymes each catalytic center participates only once and there is no enzyme turnover. A systematic kinetic analysis of irreversible inhibition of these enzyme reactions is presented. Based on the algebraic criteria proposed in this work, it should be possible to evaluate either the mechanism of inhibition (complexing or non-complexing), or the type of inhibition (competitive, non-competitive, uncompetitive, mixed non-competitive). In addition, all kinetic constants involved in each case could be calculated. An experimental application of this analysis is also presented, concerning peptide bond formation in vitro. Using the puromycin reaction, which is a model reaction for the study of peptide bond formation in vitro and which follows the same kinetic law as the enzymes under study, we have found that: (i) the antibiotic spiramycin inhibits the puromycin reaction as a competitive irreversible inhibitor in a one step mechanism with an association rate constant equal to 1.3 x 10(4) M-1 s-1 and, (ii) hydroxylamine inhibits the same reaction as an irreversible non-competitive inhibitor also in a one step mechanism with a rate constant equal to 1.6 x 10(-3) M-1 s-1.

Acyltransferases↗
PubMed2006

Protective effect of radical scavenger edaravone against puromycin nephrosis.

AIM: Recent studies have indicated that reactive oxygen species (ROS) play a role in the pathogenesis of glomerular injury leading to proteinuria in nephrotic syndrome. In the present investigation, we examined the effects of the radical scavenger edaravone administered at various time points to rats with puromycin nephrosis. MATERIALS AND METHODS: 35 Wistar rats were divided into five groups: treatment with puromycin aminonucleoside (PAN) alone, treatment with PAN followed by edaravone in the early period, treatment with PAN followed by edaravone administration in the late period, treatment with PAN and administration of edaravone for the whole experimental period, and untreated controls. On Days 3, 6 and 9, urinary protein excretion was measured. The levels of glomerular thiobarbituric acid-reactive substance (TBArs) were determined in all animals on Day 10. RESULTS: On Day 9, rats that had been administered edaravone showed reduced urinary protein excretion and reduced glomerular TBArs. In particular, edaravone administration in the late period, during which proteinuria was most acute, had the effect of reducing the severity of proteinuria. Glomerular TBArs were suppressed to the control level. Our results indicate that edaravone exerts a protective effect in the acute phase of PAN nephrosis when administered as antioxidant therapy at the onset of proteinuria. CONCLUSIONS: Edaravone can ameliorate urinary protein excretion after the onset of proteinuria in nephrotic syndrome.

Animals↗
PubMedDate not supplied

[Resin linked puromycin (author's transl)].

A biospecific resin for the retardation of ribosomal peptodyltransferase by affinity chromatography was prepared by condensing the alpha-amino group of puromycin with the N-hydroxysuccinimide ester of CH-Sepharose 4B to yield the resin-linked puromycin derivative 4.

Acyltransferases↗
PubMed1992

Renal extracellular matrix accumulation in acute puromycin aminonucleoside nephrosis in rats.

Progressive renal fibrosis is considered to be the final common pathway leading to chronic renal insufficiency. In this study, the authors examined some of the cellular and molecular mechanisms regulating the renal accumulation of extracellular matrix (ECM) proteins using rats with puromycin amino-nucleoside (PAN) nephrosis as an acute model system. Puromycin aminonucleoside rats developed reversible nephrotic syndrome accompanied by an interstitial infiltrate of monocytes. The number of interstitial fibroblasts expressing ST4 antigen did not increase. During the first 4 days, steady-state mRNA levels for all genes examined remained at or below control levels. At 1 week, nephrotic syndrome and interstitial inflammation were established, and a period of renal cell proliferation occurred, identified by increased histone mRNA levels and localized by tritiated thymine autoradiography to tubular epithelial cells and occasional interstitial cells. Transforming growth factor-beta (TGF-beta) steady-state mRNA levels were increased eightfold, but returned to control levels by 3 weeks. At week 1, there was a 10- to 20-fold increase in kidney steady-state mRNA levels for genes encoding interstitial matrix proteins collagen I and fibronectin and basement membrane collagen IV. By in situ hybridization, alpha 1(I) procollagen mRNA was localized to interstitial cells. Immunofluorescence microscopy demonstrated focal accumulation of ECM proteins in the tubulointerstitial compartment at 2 and 3 weeks, but by 6 weeks, kidney immunohistology was normal again. Steady-state mRNA levels for the matrix degrading metalloproteinase stromelysin remained at control values, whereas the levels for interstitial collagenase were normal at week 1 and increased twofold to threefold at 2 and 3 weeks. Steady-state mRNA levels for the tissue inhibitor of metalloproteinases (TIMP) increased fivefold at 1 week and returned to baseline values over the next 2 weeks. The results of this study suggest that tubulointerstitial ECM accumulation occurs in rats with acute PAN nephrosis because of the activation of genes encoding several matrix proteins and inhibition of matrix degradation mediated by TIMP. These events are reversed during the phase of recovery from nephrotic syndrome. Increased mRNA levels for TGF-beta, possibly originating from inflammatory interstitial monocytes, are likely to be one of the mediators of the molecular events observed.

Animals↗
PubMed2005

Increased expression of apoptosis-associated proteins in puromycin aminonucleoside nephrosis.

Increased apoptosis has been reported in acute puromycin aminonucleoside nephrosis (PAN). The aim of this study was to investigate if increased apoptosis is related to increased expression of apoptosis-associated proteins (AAP) in this model of nephrosis. Sprague-Dawley rats were made nephrotic by intraperitoneal injection of one dose of puromycin aminonucleoside. Renal tissues were obtained at 1, 2 and 7 weeks after injection and apoptosis was investigated by TUNEL and by electron microscopy. Fas, Fas ligand, p53, Bax and Bcl-2 expressions were analyzed by the respective monoclonal and polyclonal antibodies, using indirect immunofluorescence. In the glomerulus of nephrotic animals, increased apoptosis was accompanied with increased expression of p53, Fas and Bax. In the interstitium, high expression of apoptosis, Fas, Fas-L and Bax were observed and in tubules increased apoptosis was accompanied with increased expression of p53, Fas and Fas-L. Bcl-2 was increased in interstitium and tubules during PAN. The incidence of apoptosis during PAN was correlated with the expression of AAP in glomerulus (p53), interstitium (Fas, Fas-L and Bax) and tubules (Fas, Fas-L, p53 and Bcl-2). There was correlation between Fas and Fas-L expression in interstitium and tubules. About 4% of glomerular and 25% of tubular p53 positive cells were apoptotic cells. The data suggest that increased local expression of AAP could contribute to renal apoptosis in the glomerular, interstitial and tubular compartments during this experimental model of nephrosis.

Animals↗
PubMed1991

Ultrastructural alterations of pulmonary surfactant in rat lungs after inhibition of protein synthesis by puromycin.

The effects of systematically administered puromycin on the fine structure of the lung were studied. The effects varied depending on the duration of exposure and the time interval between the last injection and sacrifice. After short term exposure most surfactant had separated from the epithelial surface and profound alterations in the tubular myelin structure were seen. After moderate duration of exposure a previously undescribed multilamellar lining layer was observed which was often detached from the alveolar epithelium. Six hours after the last injection the regular tubular myelin pattern reappeared. Puromycin treatment results in inhibition of various proteins synthesized by type II epithelial cells. Inhibition of synthesis of some proteins, most probably that of glycoprotein A, causes a primary effect on the structure of surfactant. The loss of at least some of the cytoskeletal proteins in Type II epithelial cells apparently results in interference with exocytosis of lamellar body contents.

Animals↗
PubMed1978

Effect of thyroid hormone, actinomycin D, cycloheximide and puromycin on TRH-induced secretion of TSH, as studied by pituitary concentration of cyclic AMP and intrathyroidal colloid droplet formation.

In an attempt to study the functional relation between pituitary cyclic AMP and TSH secretion in response to thyrotropin releasing hormone (TRH) or thyroid hormone administration, pituitary concentration of cyclic AMP was measured by protein binding assay after in vivo and in vitro administration of test materials (TRH, thyroxine, triiodothyronine, actinomycin D, puromycin and cycloheximide singly or in combination). Small dose of TRH apparently augmented TSH secretion as evidenced by a marked increase of intrathyroidal colloid droplet, but failed to elevate the pituitary concentration of cyclic AMP. Triiodothyronine (T3) and thyroxine (T4) blocked an increase of TSH secretion produced by TRH, but they elevated pituitary concentration of cyclic AMP in vivo and in vitro. Actinomycin D (Act D), puromycin and cycloheximide elevated pituitary cyclic AMP concentration without stimulating TSH secretion. From the data accumulated, it appears that the measurement of total anterior pituitary concentration of cyclic AMP is not useful to evaluate the activity of TSH cells in response to thyroid hormone, TRH and TRH plus thyroid hormone.

Animals↗
PubMed1990

Endocytosis of cationized horseradish peroxidase by glomerular epithelial cells is reduced in puromycin glomerulopathy.

Rats were treated with a single intravenous injection of aminonucleoside of puromycin and were sacrificed between 1 and 21 days after injection. The conjugate of horseradish peroxidase with a poly-L-lysine (HRP.PL) was used to reveal endocytotic activity in glomerular epithelial cells (GEC). This conjugate was injected intravenously 2 h before each sacrifice. Renal tissue was taken and treated cytochemically with a conventional DAB technique and observed by light and electron microscopy. The assessment of endocytosis by glomerular epithelial cells was performed on 1-micron sections by counting HRP.PL grains in the GEC and expressing this in terms of the area of glomerulus examined. The results were compared to those found in normal rats. Our results show that GEC endocytotic function was reduced during the whole period of the experiment. It fell quickly from 1 day after puromycin injection and reached the most marked reduction on the 4th day, preceding the peak of proteinuria which was between 7 and 12 days. From the 5th day onward the endocytotic function gradually recovered, but was still abnormal at the end of the experiment.

Animals↗
PubMed1987

Stable analogs of prostaglandins E1 and F2 alpha ameliorate the proteinuria of aminonucleoside-of-puromycin nephrosis in Lewis rats.

Prostaglandins have been implicated by previous investigators in the pathogenesis of the nephrotic syndrome. A single subcutaneous injection of 1 mg/kg of stable analogs of prostaglandins E1 or F2 alpha (15[S]-15-methyl -PGE1 [M-PGE1] and -PGF2 alpha [M-PGF2 alpha]) was found in the present study to dramatically decrease proteinuria on Day 10 of puromycin aminonucleoside (PAN) nephrosis in Lewis rats. The decrease in proteinuria was mediated at least in part by a decrease in glomerular filtration rate (GFR), as quantitated by inulin clearances in nephrotic control and prostaglandin-treated rats. M-PGE1, moderately, and M-PGF2 alpha, to a lesser degree, also decreased the GFR in normal rats. Interestingly, the GFR was dramatically decreased in nephrotic as compared with nonnephrotic control rats, which suggests that PAN nephrosis may not be an ideal experimental model for human minimal change nephrosis in which the GFR is usually not severely compromised. The prostaglandin-induced decrease in GFR in both nephrotic and normal rats was coincident with a drop in systemic blood pressure. Nephrotic rats, however, had a slightly higher baseline blood pressure than normals, and the hypotensive effects of both prostaglandins were much less in nephrotic than in normal rats. The decrease in proteinuria was not related to a cytoprotective effect, as indicated by the failure of daily doses of 5 micrograms/kg M-PGE1 to reduce proteinuria 6, 8, or 10 days after injection of puromycin aminonucleoside. The similar antiproteinuric effects of prostaglandin synthesis inhibitors and of pharmacologic doses of prostaglandins are somewhat paradoxical but are reminiscent of the similarly paradoxical mutual antiinflammatory effects of these agents. The high doses of prostaglandins required to reduce proteinuria as well as their reduction of blood pressure and GFR will limit their clinical usefulness in the nephrotic syndrome.

Alprostadil↗
PubMed1985

Inhibitors of protein synthesis, puromycin and emetine, inhibit prostaglandin E2 release by skeletal muscle.

Addition of 1 microM puromycin or 1 microM emetine to rat soleus muscle in vitro decreases muscle prostaglandin E2 release by 51-77%. This inhibition appears to be caused by decreased availability of endogenous arachidonic acid for prostaglandin E2 synthesis, because neither puromycin nor emetine inhibits muscle prostaglandin E2 production from arachidonic acid added into the incubation medium.

Animals↗
PubMed1980

[Morphogenesis of the embryonic head of the chicken following treatment of the isolated brain with actinomycin D and puromycin. First observations].

Isolated brains of 40 hours-old chick embryos are treated by actinomycin D or puromycin solutions at various concentrations and during a relatively short time. Actinomycin D induced ocular malformations varying from subnormal types to anophthalmy. Above a certain concentration, it inhibits lens development. Puromycin is less powerful and determines microphthalmy and synophthalmy, with lens formation in all cases. It seems that actinomycin D could diffuse from the brain to the optic vesicles and inhibit their inductive influence upon the lentogen placodes.

Abnormalities, Drug-Induced↗
PubMed1982

Effect of indomethacin on lymphocyte response to mitogens in puromycin aminonucleoside nephrosis in the rat.

The mitogen response of peripheral blood lymphocytes to phytohaemagglutinin is depressed in rats with nephrotic syndrome induced by the administration of the aminonucleoside of puromycin. The mitogen response is normal after the administration of aminonucleoside of puromycin, but before the nephrotic syndrome develops. Nephrotic syndrome serum depresses the mitogen response of normal lymphocytes. This effect is attenuated by treatment of nephrotic rats with indomethacin, independently of any change in plasmas albumin concentration. Indomethacin in vitro has no effect. These studies suggest that the impaired response of nephrotic lymphocytes to phytohaemagglutinin is a secondary consequence of the nephrotic state, probably attributable, at least in part, to increased prostaglandin production in the nephrotic syndrome.

Animals↗
PubMed1981

Effect of narciclasine and puromycin on the synthesis of rapidly labelled RNA in excised salivary glands of Chironomus thummi.

The effect on transcription of two protein synthesis inhibitors, narciclasine and puromycin, when applied in short periods of time to explanted salivary glands of Chironomus thummi, has been studied. Narciclasine (6 muM) enhances the uptake of uridine and stimulates the synthesis of giant-heterogeneous, pre-ribosomal (38 S) and low-molecular weight (4-5 S) RNA. However, puromycin (200 muM) inhibits uridine uptake and decrease selectively the synthesis of pre-rRNA, while transcription of low-molecular weight RNA is stimulated. These effects are compared with those previously found to be produced by other inhibitors of translation in this biological system.

Alkaloids↗