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J Pfeilschifter

Publications and source records attributed to J Pfeilschifter.

At least 127 records · Page 7Linked to original sources
PubMed1997

[Prevalence of thyroid gland dysfunctions in 50- to 80-year-old patients. An epidemiologic cross-sectional study in a southwestern community].

BACKGROUND: Thyroid dysfunctions in the elderly are common in iodine deficient Germany. However, the exact prevalence of hypo- and hyperthyroidism is unknown and differs according to the composition of the screened population. In this study we examined the prevalence of thyroid disorders in a population based sample of non-hospitalized elderly people living in a community in southwestern Germany. PATIENTS AND METHODS: In the context of an epidemiological study on the prevalence of osteoporosis and associated factors, 288 men and 271 women between the age of 50 and 80 years were screened for plasma levels of thyreotropin, free T3 and free T4. Participants received an interview on medical conditions including a history on thyroid disorders. RESULTS: 6.7% of the women and 1.7% of the men had a history of thyroid surgery. Manifest or treated hyperthyroidism was observed in 3.5% of the women (n = 10) and 0.7% of the men (n = 2). In 2 of 12 patients with manifest hyperthyroidism the condition was previously unknown. 70- to 80-year old women tended to have a higher prevalence of hyperthyroidism (6.3%) than 50- to 59-year old women (2.9%), or 60- to 69-year old women (3.4%). Subclinical hyperthyroidism was observed in 7.3% of the men (n = 21) and 5.9% of the women (n = 16). We observed no cases of over hypothyroidism in men but in 1.8% of the women (n = 5). Four of 5 manifest states of hypothyroidism were previously unknown. CONCLUSION: The prevalence of thyroid dysfunction in older women and men living in southwestern Germany is high. In view of the often nonspecific clinical symptoms of hypo- and hyperthyroidism in elderly individuals, thyroid disorders should be early included to the list of the differential diagnosis of clinical complaints in this age group.

Aged↗
PubMed1997

Cross-talk between secretory phospholipase A2 and cytosolic phospholipase A2 in rat renal mesangial cells.

Incubation of rat glomerular mesangial cells with potent proinflammatory cytokines like interleukin 1beta, (IL- 1beta) triggers the expression of a non-pancreatic secretory phospholipase A2 (sPLA2) and increases the formation of prostaglandin E2. We show here that sPLA2 acts in an autocrine fashion on mesangial cells and induces a rapid activation of protein kinase C (PKC) isoenzymes delta and epsilon and of p42 mitogen-activated protein kinase (MAPK), two putative activators of cytosolic phospholipase A2 (cPLA2). sPLA2 also activates Raf-1 kinase in mesangial cells which integrates the signals coming from PKC for further processing along the MAPK cascade. Subsequently a phosphorylation and activation of cPLA2 is observed, thus arguing for a cross-talk between the two classes of PLA2. Pretreatment of cells with either the highly specific PKC inhibitor Ro-318220 or the highly specific MAPK kinase (MEK) inhibitor PD 98059 completely blocked the sPLA2-induced cPLA2 activation, indicating that both kinases are essential for the cross-talk between the two types of PLA2. The effect of sPLA2 is mimicked by lysophosphatidylcholine (LPC), a reaction product of sPLA2 activity. LPC stimulates PKC-epsilon, Raf-1 kinase and MAPK activation as well as cPLA2 activation with a subsequent increase in arachidonic acid release from mesangial cells. These data suggest that sPLA2 by cleaving membrane phospholipids and generating LPC and other lysophospholipids activates cPLA2 via the PKC/Raf-1/MAPK signalling pathway. Hence a network of interactions between different PLA2s is operative in mesangial cells and may contribute to the progression of glomerular inflammatory processes.

Animals↗
PubMed1997

Mechanisms of suppression of inducible nitric-oxide synthase (iNOS) expression in interferon (IFN)-gamma-stimulated RAW 264.7 cells by dexamethasone. Evidence for glucocorticoid-induced degradation of iNOS protein by calpain as a key step in post-transcriptional regulation.

The murine macrophage cell line RAW 264.7 expresses inducible nitric-oxide synthase (iNOS) activity upon stimulation with interferon (IFN)-gamma and/or bacterial lipopolysaccharide. We have studied the mechanisms by which the synthetic glucocorticoid dexamethasone suppresses IFN-gamma-stimulated iNOS expression in RAW 264.7 cells. Treatment of cells with dexamethasone reduces the formation of nitrite, one of the stable end products of NO production measured in culture supernatants with an IC50 of 9 nM. The reduction of iNOS activity is caused by decreased iNOS protein levels as assessed by immunoblotting using a specific anti-iNOS antibody. Dexamethasone treatment also reduces the formation of iNOS mRNA steady state levels to about 50% in IFN-gamma-stimulated cells. This is due to decreased iNOS gene transcription and iNOS mRNA stability. More importantly, dexamethasone reduces the amount of iNOS protein by two additional mechanisms: reduction of the translation of iNOS mRNA and increased degradation of the iNOS protein. Using a specific protease inhibitor for the cysteine protease calpain I, N-acetyl-Leu-Leu-norleucinal (calpain inhibitor I), the enhanced proteolysis of the iNOS protein can efficiently be blocked, whereas other protease inhibitors such as tosyl-L-lysine chloromethyl ketone have no effect. Dexamethasone does not significantly alter calpain gene expression. Northern blot analyses reveal that calpain mRNA steady state levels are virtually not affected upon incubation of the cells with IFN-gamma and dexamethasone. Immunoprecipitation using a polyclonal anti-calpain antibody reveals that calpain protein levels are also not affected by the glucocorticoid. This is the first evidence that the iNOS protein is a molecular target for the cysteine protease calpain.

Animals↗
PubMed1997

The balance between nitric oxide and superoxide determines apoptotic and necrotic death of rat mesangial cells.

Nitric oxide (NO.) and superoxide (O2-) are inflammatory mediators. Their formation seems to be associated with apoptotic and/or necrotic cell death in diseases such as mesangioproliferative glomerulonephritis in which the early phase of mesangiolysis is linked to significant NO. production. Notably, mesangial cells (MC) not only generate NO. but also O2- after cytokine stimulation. Here we investigated the interrelation between NO. and O2- in MC death by generating both radicals with the use of NO donors (S-nitrosoglutathione, spermine-NO) and O2(-)-generating systems (2,3-dimethoxy-1,4-naphtoquinone, hypoxanthine/xanthine oxidase). Exogenously supplied NO. or O2- in a concentration-dependent manner induced apoptosis and/or necrosis. Apoptosis is characterized by chromatin condensation and DNA fragmentation in contrast to necrotic cytoplasmatic membrane rupture. Noteworthy, coincubation of NO. and O2- was cross-protective. Maximum protection required the existence of a balanced NO./O2- ratio. Analysis in cytokine-stimulated MC suggests endogenous radical formation, which may participate in modulating apoptosis. Manipulation of the endogenous NO./O2- ratio by exogenous, sublethal S-nitrosoglutathione in addition to cytokines produced death, which was antagonized by inducible nitric oxide synthase (iNOS) inhibition. Moreover, pyrrolidine dithiocarbamate supplementation, which down-regulates iNOS expression and blocks superoxide dismutase activity, initiates apoptosis. Our results imply the participation of reactive nitrogen and oxygen species in determining life and death of MC.

Animals↗
PubMed1997

Activation of protein kinase C subtypes alpha, gamma, delta, epsilon, zeta, and eta by tumor-promoting and nontumor-promoting agents.

Protein kinase C (PKC) subtypes alpha, gamma, delta, epsilon, zeta, and eta have been expressed using the baculovirus expression system. The partially purified PKC subtypes have been studied for their substrate specificities and phospholipid-independent activation by various chemically different nontumor- and tumor-promoting agents, as well as their inhibition of kinase activity by staurosporine and two related compounds. An endogenous PKC-like kinase activity of Sf9 cells was detected and analyzed for cofactor requirements and inhibition. Protamine sulfate was most efficiently phosphorylated by all of the PKC subtypes tested, although this phosphorylation was independent of phosphatidylserine (PS) and diacylglycerol (DAG) or 12-O-tetradecanoylphorbol 13-acetate (TPA). Except for PKC-zeta, all subtypes tested phosphorylated myelin basic protein (MBP), histone, or a peptide derived from the pseudosubstrate region of PKC-alpha in a PS/DAG-dependent manner but to varying extents. Among the various agents tested, TPA most efficiently stimulated the kinase activities of the PKC subtypes in a phospholipid-dependent manner. Phorbol 12,13-dibutyrate (PDBu) was less effective than TPA but displayed no major difference among the subtypes. Activation of PKC-alpha by bryostatin-1 reached only half of the TPA response whereas the other subtypes were activated more effectively. The weak tumor promoter resiniferonol 9,13,14-orthophenyl acetate (ROPA) mainly stimulated PKC-alpha and PKC-gamma at 1 microM concentration, whereas PKC-epsilon and PKC-eta were much less activated. Sapintoxin D, mezerein, indolactam V, and resiniferatoxin at concentrations of 1-100 nM preferentially activated PKC-alpha in a DAG-like manner, whereas at 1 microM other subtypes were activated as well. Preferential activation of PKC-alpha was also noted for tinyatoxin and thapsigargin, but their mode of activation is unclear because these two compounds did not compete for the phorbol ester binding of the PKC subtypes as the other agents did. Of the three PKC inhibitors tested, staurosporine most efficiently inhibited kinase activity of the PKC subtypes, whereas K252a and CGP 41251 were at least 10 times less effective. However, K252a showed certain specificity for inhibition of PKC-alpha, and CGP 41251 failed to inhibit PKC-epsilon and PKC-zeta. Given the different substrate specificities and modes of activation by various tumor-promoting and nontumor-promoting agents, as well as the different sensitivities towards different inhibitors, our results indicate a divergence of individual PKC subtypes in signal transduction.

Animals↗
PubMed1997

Transforming growth factor-beta 2 inhibits interleukin 1 beta-induced expression of inducible nitric oxide synthase in rat renal mesangial cells.

OBJECTIVE AND DESIGN: We have investigated whether transforming growth factor beta 2 (TGF-beta 2) influences the expression of inducible nitric oxide synthase (iNOS). MATERIAL: Rat renal mesangial cells exposed to the inflammatory cytokine interleukin 1 beta (IL-1 beta). RESULTS: Addition of TGF-beta 2 dose-dependently suppresses IL-1 beta-induced nitrite formation. Western and Northern blot analyses of mesangial cell extracts reveal that the inhibition of IL-1 beta-induced nitrite formation by TGF-beta 2 is due to decreased iNOS protein and iNOS mRNA steady state levels. Reduction of iNOS mRNA levels is due to decreased transcriptional activity of the iNOS gene under the action of TGF-beta 2 as shown by nuclear run on experiments. CONCLUSIONS: TGF-beta 2 is a potent inhibitor of iNOS expression acting by reducing the transcriptional activity of the iNOS gene.

Animals↗
PubMed1997

Feedback regulation of extracellular ATP-stimulated phosphoinositide hydrolysis by protein kinase C-alpha in bovine glomerular endothelial cells.

In glomerular endothelial cells, extracellular ATP stimulates a phospholipase C with subsequent hydrolysis of polyphosphoinositides and an increase in cytosolic free Ca2+ concentration ([Ca2+]i). Short-term (30 min) pretreatment of endothelial cells with 12-O-tetradecanoylphorbol 13-acetate (TPA), a potent activator of protein kinase C (PKC), decreases the ATP-stimulated phosphoinositide degradation and Ca2+ mobilization. However, this inhibition was lost after incubating the cells for four hours with TPA. Longer-term pretreatment (10 to 48 hr) even potentiated ATP-induced phosphoinositide breakdown and Ca2+ mobilization. In addition, pretreating the cells for 30 minutes with the specific PKC inhibitor Ro 31-8220 dose-dependently increased ATP-stimulated phosphoinositide hydrolysis, thus clearly indicating a regulatory role for PKC in the inositol lipid signaling pathway in glomerular endothelial cells. By using specific antibodies recognizing the different PKC isoenzymes, it is observed that glomerular endothelial cells express five isoenzymes: PKC-alpha, -delta, -epsilon, -zeta and -theta. No PKC-beta, -gamma, -eta and -mu isoenzymes were detected. On exposure to TPA, a complete depletion of PKC-alpha is observed within four hours. In contrast, PKC-epsilon was more resistant to phorbol ester, and even after 48 hours of TPA treatment, only 60% of PKC-epsilon was down-regulated. PKC-theta decreased very slowly from the cytosol (47% left after 24 hr of phorbol ester treatment) and translocated to the Triton X100-insoluble fraction. Moreover, PKC-delta and PKC-zeta were not significantly affected by 48 hours of phorbol ester incubation. Thus, only PKC-alpha is depleted with a kinetic that corresponds to the loss of feedback inhibition of ATP-stimulated phosphoinositide turnover. In the next step, [Ca2+]i changes were measured in single cells loaded with Fura-2 after microinjection of neutralizing PKC isoenzyme-specific antibodies. Injection of antibodies specific for PKC-alpha potently increased Ca2+ mobilization in response to ATP stimulation when compared to cells injected with buffer only or antibodies specific for PKC-epsilon. These results provide evidence that PKC-alpha mediates feedback inhibition of ATP-stimulated phosphoinositide hydrolysis in glomerular endothelial cells.

Adenosine Triphosphate↗
PubMed1997

Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis.

During proliferative glomerulonephritis, the early phase of mesangiolysis is linked to increased nitric oxide (NO) production. NO. as well as superoxide (O2-) are inflammatory mediators that are generated by mesangial cells (MC) after cytokine stimulation. Added individually, both radicals induce MC apoptosis. However, the co-existence of a defined NO./O2- ratio is cross-protective. Apoptosis is characterized by specific features such as chromatin condensation, DNA strand breaks, and the occurrence of apoptotic regulating proteins. The tumor suppressor p53 and Bax (Bcl-2 associated protein x) are considered to be classical death promotors, which accumulate after toxic insults. To study p53 and Bax protein accumulation in NO. and/or O2(-)-induced apoptosis, we used the NO-donor S-nitrosoglutathione (GSNO) and the redox cycler 2,3-dimethoxy-1,4-naphtoquione (DMNQ). Both agonists initiated DNA fragmentation in a concentration dependent manner associated with transient p53 and Bax up-regulation. Co-generation of NO./O2- resulted not only in reduced DNA fragmentation, but also in decreased Bax accumulation. Comparable to the NO./O2- co-generation, cytokines failed to induce apoptosis. In contrast, cytokines in combination with pyrrolidine dithiocarbamate, which blocks endogenous superoxide dismutase, allowed p53 and Bax accumulation as well as DNA fragmentation. Our results demonstrate p53 and Bax as early components in NO. and O2(-)-induced rat MC apoptosis and point to the NO./O2- interaction as a naturally occurring cell defense mechanism.

Animals↗
PubMed1997

Stimulation by extracellular ATP and UTP of the stress-activated protein kinase cascade in rat renal mesangial cells.

1. Extracellular adenosine 5'-triphosphate (ATP) and uridine 5'-triphosphate (UTP) have been shown to activate a nucleotide receptor (P2U receptor) in rat mesangial cells that mediates phosphoinositide and phosphatidylcholine hydrolysis by phospholipases C and D, respectively. This is followed by an increased activity of the mitogen-activated protein kinase cascade and cell proliferation. Here we show that ATP and UTP potently stimulate the stress-activated protein kinase pathway and phosphorylation of the transcription factor c-Jun. 2. Both nucleotides stimulated a rapid (within 5 min) and concentration-dependent activation of stress-activated protein kinases as measured by the phosphorylation of c-Jun in a solid phase kinase assay. 3. When added at 100 microM the rank order of potency of a series of nucleotide analogues for stimulation of c-Jun phosphorylation was UTP > ATP = UDP = ATP gamma S > 2-methylthio-ATP > beta gamma-imido-ATP = ADP > AMP = UMP = adenosine = uridine. Activation of stress-activated protein kinase activity by ATP and UTP was dose-dependently attenuated by suramin. 4. Down-regulation of protein kinase C-alpha, -delta and -epsilon isoenzymes by 24 h treatment of the cells with 12-O-tetradecanoylphorbol 13-acetate did not inhibit ATP- and UTP-induced activation of c-Jun phosphorylation. Furthermore, the specific protein kinase C inhibitors, CGP 41251 and Ro 31-8220, did not inhibit nucleotide-stimulated c-Jun phosphorylation, suggesting that protein kinase C is not involved in ATP- and UTP-triggered stress-activated protein kinase activation. 5. Pretreatment of the cells with pertussis toxin or the tyrosine kinase inhibitor, genistein, strongly attenuated ATP- and UTP-induced c-Jun phosphorylation. Furthermore, N-acetyl-cysteine completely blocked the activation of stress-activated protein kinase in response to extracellular nucleotide stimulation. 6. In summary, these results suggest that ATP and UTP trigger the activation of the stress-activated protein kinase module in mesangial cells by a pathway independent of protein kinase C but requiring a pertussis toxin-sensitive G-protein and tyrosine kinase activation.

Acetylcysteine↗
PubMed1997

Suppression by cyclosporin A of interleukin 1 beta-induced expression of group II phospholipase A2 in rat renal mesangial cells.

1. We investigated whether cyclosporin A, a potent immunosuppressive drug, affects group II phospholipase A2. (PLA2; EC 3.1.1.4) induction in rat renal mesangial cells. 2. Previously we showed that the expression of group II PLA2 in rat renal mesangial cells is triggered by exposure of the cells to inflammatory cytokines such as interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha and agents that elevate cellular levels of cyclic AMP. Treatment of mesangial cells with IL-1 beta for 24 h induced PLA2 activity secreted into cell culture supernatants by about 16 fold. Incubation of mesangial cells with cyclosporin A inhibited IL-1 beta-induced PLA2 section in a dose-dependent fashion, with an IC50 value of 4.3 microM. Cyclosporin A did not directly inhibit enzymatic activity of PLA2. 3. Immunoprecipitation of radioactively labelled PLA2 protein from mesangial cell supernatants revealed that the inhibition of PLA2 activity is due to a suppression of PLA2 protein levels. This effect was preceded by a reduction of PLA2 mRNA steady state levels, as demonstrated by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells. 4. In order to evaluate whether cyclosporin A would affect the transcriptional activity of the PLA2 gene, we performed nuclear run on transcription experiments and provided evidence that the transcription rate of the PLA2 gene is reduced by cyclosporin A. 5. Previously we found that the nuclear transcription factor kappa B (NF kappa B) is an essential component of the IL-1 beta-dependent upregulation of PLA2 gene transcription. By electrophoretic mobility shift analysis, we demonstrated that cyclosporin A diminishes the formation of NF kappa B DNA-binding complexes, thus suggesting that this transcription factor is a target for cyclosporin A-mediated repression of PLA2 gene transcription. 6. The data presented in this study strongly suggest that the cellular mechanism involved in the IL1 beta-dependent transcriptional upregulation of the PLA2 gene in mesangial cells is a target for the action of cyclosporin A.

Animals↗
PubMed1997

Differential effect of dexamethasone on interleukin 1beta- and cyclic AMP-triggered expression of GTP cyclohydrolase I in rat renal mesangial cells.

1. Endogenous synthesis of tetrahydrobiopterin (BH4) is an essential requirement for cytokine-stimulated nitric oxide (NO) synthesis in rat mesangial cells. GTP cyclohydrolase I, the rate-limiting enzyme in BH4 synthesis, is expressed in renal mesangial cells in response to two principal classes of activating signals. These two groups of activators comprise inflammatory cytokines such as interleukin (IL)-1beta and agents that elevate cellular levels of cyclic AMP. 2. We examined the action of the potent anti-inflammatory drug dexamethasone on GTP cyclohydrolase I induction in response to IL-1beta and a membrane-permeable cyclic AMP analogue, N6, O-2'-dibutyryladenosine 3'-5'-phosphate (Bt2cyclic AMP). 3. Nanomolar concentrations of dexamethasone markedly attenuated IL-1beta-induced GTP cyclohydrolase I mRNA steady state level as well as IL-1beta-induced GTP cyclohydrolase I protein expression and enzyme activity. In contrast, dexamethasone did not inhibit Bt2cyclic AMP-triggered increase in GTP cyclohydrolase I mRNA level and protein expression, and low (1 nM) or high (1 and 10 microM) doses of dexamethasone consistently increased Bt2cyclic AMP-induced GTP cyclohydrolase activity. 4. In summary, these results suggest that glucocorticoids act at several levels, critically dependent on the stimulus used, to control GTP cyclohydrolase I expression.

Animals↗
PubMed1997

Suppression of serum thyrotropin with thyroxine in patients with Graves' disease: effects on recurrence of hyperthyroidism and thyroid volume.

Based on findings that thyroxine may have a beneficial effect on the recurrence of Graves' hyperthyroidism, we prospectively studied the effects of a TSH suppressive treatment with thyroxine on the course of Graves' disease in fifty patients with recent onset of hyperthyroidism. After the normalization of serum tri-iodothyronine (T3) and thyroxine (T4) concentrations, one group of patients was randomly assigned to a combined treatment with carbimazole and a TSH suppressive dose of T4 for 12 months, followed by another 12 months of TSH suppressive therapy alone. The other group of patients also received carbimazole for one year, but T4 was only added as indicated to normalize elevated TSH serum concentrations, and patients received no therapy during the second year. By the end of the second year, a relapse of hyperthyroidism had occurred in 43% of the patients with and in 45% of the patients without suppressive T4 treatment. In those patients without a relapse of hyperthyroidism, initial thyroid size significantly (P = 0.01) decreased with time in both treatment groups. However, patients on suppressive T4 treatment tended to have a greater reduction in thyroid volume than patients with normal TSH serum concentrations (P = 0.05). In conclusion, we were unable to detect a preventive effect of exogenous TSH suppression on the recurrence of hyperthyroidism. However, our data suggest that TSH suppressive treatment may have a beneficial effect on thyroid enlargement in Graves' disease.

Adrenergic beta-Antagonists↗
PubMed1997

Apoptosis and expression of inducible nitric oxide synthase are mutually exclusive in renal mesangial cells.

Nitric oxide (NO) is a multipurpose messenger molecule, important for blood vessel relaxation, neuronal communication, and antimicrobial activities. The generation of NO from L-arginine is catalyzed by NO synthase (NOS). An inducible form of NOS, iNOS, was first characterized in macrophages and then in many other tissues and cells, including renal mesangial cells. Mesangial cells play a crucial role in the regulation of the glomerular filtration rate as well as in the pathophysiology of certain forms of glomerulonephritis in which mesangial cells and macrophages produce NO in high amounts. Because reports have associated NO production with apoptotic cell death in macrophages and we recently demonstrated NO-mediated apoptosis in mesangial cells, we searched for the relationship between in situ iNOS induction and apoptosis by iNOS immunocytochemistry and terminal desoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. RAW 264.7 macrophages exhibited homogeneous iNOS expression and apoptotic nuclei in the iNOS-containing cells upon stimulation with interferon-gamma and lipopolysaccharide. In contrast, stimulated rat mesangial cells stained heterogeneously for iNOS, depending on cell passage and iNOS-stimulating pathway. Mesangial cells expressing iNOS did not display signs of apoptosis and, vice versa, cells showing characteristic features of apoptosis did not stain for iNOS. Thus, our study suggests that mesangial cells react to stimulation by interleukin-1 and/or cAMP-elevating compounds with mutually exclusive responses, either by expression of iNOS or by undergoing programmed cell death.

Animals↗
PubMed1997

[Impact of pretreatment variables on the outcome of standardized 131I therapy with 150 Gray in Graves' disease].

AIM: We examined the impact of several pretreatment variables on thyroid size and function in 61 patients with Graves' disease one year after a standardized [131]I treatment with 150 Gray. METHODS: FT3, FT4, and TSH serum concentrations were determined before and 1.5, 3, 6, and 12 months after therapy. Thyroid size was measured by ultrasound and scintigraphy before and one year after therapy. RESULTS: One year after therapy, 30% of the patients had latent or manifest hyperthyroidism, 24% were euthyroid, and 46% had developed latent or manifest hypothyroidism. Age and initial thyroid volume were major predictors of post-therapeutical thyroid function. Thus, persistent hyperthyroidism was observed in 70% of the patients age 50 years and older with a thyroid size of more than 50 ml. With few exception, thyroid size markedly decreased after therapy. Initial thyroid size and age were also major predictors of posttherapeutical thyroid volume. Thyroid size normalized in all patients younger than 50 years of age, independent from initial thyroid size. CONCLUSION: Radioiodine treatment with 150 Gray causes a considerable decrease in thyroid size in most patients with Graves' disease. Age and initial thyroid volume are important determinants of thyroid function and size after therapy and should be considered in dose calculation.

Adult↗
PubMed1996

Nitric oxide donors induce apoptosis in glomerular mesangial cells, epithelial cells and endothelial cells.

Renal mesangial cells exposed to inflammatory cytokines produce high concentrations of nitric oxide (NO) which may exert cytotoxic actions. We report here that glomerular mesangial cells, endothelial cells and epithelial cells in culture are themselves targets for NO and undergo apoptotic cell death upon exposure to high concentrations of NO. NO generated from different NO-releasing compounds as well as NO-saturated solution induce apoptosis in all three cell types as demonstrated by internucleosomal DNA fragmentation, an enrichment of cytosolic DNA/histone complexes, an increasing number of cellular 3'-OH-fragmented DNA ends and typical nuclear chromatin condensation. Induction of apoptosis was found to be dependent on protein synthesis and is preceded by expression of the tumour suppressor gene product p53 in mesangial cells. Induction of inducible NO synthase in mesangial cells by interleukin-1 beta leads to excessive formation of NO by the cells as measured by nitrite production. However, there was no evidence for apoptotic changes in mesangial cells triggered by endogenously produced NO. Co-cultures of glomerular endothelial or epithelial cells with interleukin-1 beta-activated mesangial cells expressing inducible NO synthase do not show apoptotic alterations in endothelial or epithelial cells. Moreover, preincubation of mesangial cells with interleukin-1 beta protects the cells from apoptosis induced by subsequent addition of exogenous NO thus suggesting that interleukin-1 beta not only triggers the expression of inducible NO synthase and massive NO formation but simultaneously stimulates a protecting principle in the cells. In summary, these results suggest that exogenous NO can induce apoptosis in all three types of intrinsic glomerular cells. However, whether endogenously produced NO can fulfil this function critically depends on a balance between a yet to be defined protective mechanism and inducible NO synthase expression in mesangial cells in response to interleukin-1 beta and eventually other inflammatory cytokines.

Animals↗