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R B Sterzel

Publications and source records attributed to R B Sterzel.

At least 19 recordsLinked to original sources
PubMed1998

Decrease of blood pressure by ventrolateral medullary decompression in essential hypertension.

BACKGROUND: About 20% of adults worldwide will develop hypertension. Studies and clinical observations suggest an association between hypertension and pulsatile compression of the ventrolateral medulla oblongata by a looping artery. We investigated whether neurosurgical microvascular decompression substantially decreases blood pressure long-term in patients with severe essential hypertension. METHODS: We included eight patients who had received three or more antihypertensive drugs without adequate control of blood pressure, intolerable side-effects, or both. All patients underwent microvascular decompression at the root-entry zone of cranial nerves IX and X after neurovascular compression of the ventrolateral medulla oblongata was seen on magnetic-resonance angiography. FINDINGS: 3 months after surgery, blood pressure and antihypertensive regimens had decreased substantially in three patients. Four patients who were followed up for more than 1 year became normotensive, but their antihypertensive regimens remained the same as those at 3 months. One patient did not improve. No complications associated with decompression occurred. One patient experienced a transient vocal-cord paresis after the laryngeal part of the vagus nerve was manoeuvered during surgery. INTERPRETATION: We showed a direct causal relation between raised blood pressure and irritation of cranial nerves IX and X. A subgroup of patients with essential hypertension may exist who have secondary forms of hypertension related to neurovascular compression at the ventrolateral medulla and who may be successfully treated with decompression.

Adult↗
PubMed1998

Exogenous nitric oxide inhibits mesangial cell adhesion to extracellular matrix components.

Interactions of mesangial cells (MCs) with components of the extracellular matrix (ECM) profoundly influence the MC phenotype, such as attachment, contraction, migration, survival and proliferation. Here, we investigated the effects of exogenous nitric oxide (NO) on the process of MC adhesion to ECM molecules. Incubation of rat MCs with the NO donor S-nitroso-N-acetylpenicillamine (SNAP) dose- and time-dependently inhibited MC adhesion and spreading on various ECM substrata, being more pronounced on collagen type I than on collagen type IV, laminin or fibronectin. In contrast, SNAP did not inhibit MC adhesion to L-polylysine-coated plates. The inhibitory effects of SNAP were reduced by hemoglobin and enhanced by superoxide dismutase. The anti-adhesive action of SNAP was mimicked not only by other NO donors but also by 8-bromo-cGMP, and significantly reversed by the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ). Moreover, SNAP and 8-bromo-cGMP decreased the adhesion-induced phosphorylation of focal adhesion kinase (pp125FAK). In the presence of SNAP or 8-bromo-cGMP, adherent MCs exhibited disturbed organization of alpha-actin filaments and reduced numbers of focal adhesions, as shown by immunocytochemistry. In additional experiments with adherent MCs, it was found that exposure to SNAP or 8-bromo-cGMP for 12 and 24 hours induced detachment of MCs. The results indicate that exogenous NO interferes with the establishment and maintenance of MC adhesion to ECM components. This inhibitory NO effect is mediated predominantly by cGMP-signaling. Disturbance of MC attachment to ECM molecules could represent an important mechanism by which NO affects MC behavior in vitro and in vivo.

Animals↗
PubMed1998

Activation of purinergic P2Y2 receptors inhibits inducible NO synthase in cultured rat mesangial cells.

Cytokine-induced nitric oxide (NO) is produced on glomerular inflammation. Glomerular injury and thrombocyte aggregation result in the release of nucleotides, which may regulate induced NO synthesis in cultured rat mesangial cells (MCs). ATP (10(-3) M) inhibited 24-h nitrite production induced by lipopolysaccharide (LPS, 10 microg/ml)/interferon-gamma (IFN-gamma, 100 U/ml) by 48.2 +/- 6. 3%, as well as induction of inducible NOS (iNOS) protein and mRNA. Also, coincubation with either 10(-4) M of UTP, ATP, or ATPgammaS inhibited LPS/IFN-gamma-induced nitrite production by 29.9 +/- 5.8, 36.4 +/- 4.3, and 50.3 +/- 6.5%, respectively, indicating involvement of purinergic P2Y2 receptors. Correspondingly, cultured MCs expressed P2Y2 receptor mRNA. Agonists for other purinergic receptors [alpha,beta-methylene-ATP, 3'-O-(4-benzoyl)-benzoyl-ATP, 2-methylthio-ATP, ADP, UDP, adenosine] were ineffective. Treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA, 10(-8) M) reproduced the inhibitory effect of ATP on iNOS protein expression and nitrite inhibition (by 46.6 +/- 10. 4%). The effect of ATP or PMA was reversed by the PKC inhibitors Ro-31-8220 (10(-8) M) and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (10(-5) M), indicating that suppression of iNOS is mediated via activation of PKC through stimulated P2Y2 receptors. In conclusion, the release of purine mediators may play a critical role for iNOS expression and synthesis of NO during glomerular inflammatory disorders.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Transforming growth factor-beta in renal disease.

An extensive number of animal and clinical studies indicate that transforming growth factor-beta (TGF-beta s) play an important role in inflammatory and fibrotic diseases, including renal fibrosis. Recent mouse models harboring genetically engineered alterations in TGF-beta pathways reveal complicated mechanisms of regulation of TGF-beta activity in vivo. The purpose of this review is to present recent advances relevant to our understanding of the TGF-beta-signaling system in renal physiology and pathophysiology.

Animals↗
PubMed1997

[Egr-1 transcription factor regulates the growth of glomerular mesangium cells].

BACKGROUND: The transcriptional regulator Early growth response gene-1 (Egr-1) is rapidly and transiently induced by various mitogens in cultured rat mesangial cells (MCs). METHOD AND RESULTS: Here we show Egr-1 induction in an in vivo model of mesangioproliferative glomerulonephritis (GN). A 14.9-fold increase in Egr-1 mRNA was observed 6 days after disease induction. A concomitant increase in Egr-1 protein was demonstrated by immunocytochemistry. Egr-1 was mainly localized to the nuclei of cells in mesangial localization. To test whether Egr-1 directly regulated MC proliferation, we preincubated cultured MCs with antisense oligonucleotides directed against Egr-1. The platelet-derived growth factor (PDGF)-induced increase in Egr-1 mRNA and protein levels was inhibited by 75% and 74%, respectively. At the same time Egr-1 antisense oligonucleotides dose-dependently inhibited MC-proliferation as determined by thymidine-uptake by up to 75%. Control oligonucleotides were without effects on Egr-1 mRNA, protein or MC growth. CONCLUSION: We conclude that Egr-1 induction is a necessary step in the mitogenic signaling cascade in glomerular MCs.

Animals↗
PubMed1997

Expression of the transcriptional regulator Egr-1 in experimental glomerulonephritis: requirement for mesangial cell proliferation.

The early growth response gene-1 (Egr-1), a zinc finger transcriptional regulator, was induced in a rat model of mesangioproliferative glomerulonephritis (GN). Northern blot analysis revealed a maximal 14.9-fold increase in glomerular Egr-1 mRNA at day 6 of GN. By immunohistochemistry Egr-1 protein expression was demonstrated to be mainly confined to glomerular mesangial cells (MC). To test whether Egr-1 directly regulates MC proliferation, cultured MCs were stimulated with platelet-derived growth factor (PDGF) after preincubation with different Egr-1 antisense oligonucleotides (ASOs). PDGF-induced rise in 3H-thymidine uptake by 83% and almost completely abrogated increase in MC number. We conclude that Egr-1 induction is of critical importance for PDGF-induced mitogenic signaling in MCs, and inhibition of Egr-1 in vivo may offer an approach to oppose glomerular MC proliferation in glomerular inflammatory disease.

Animals↗
PubMed1997

TGF-beta1-induced cell cycle arrest in renal mesangial cells involves inhibition of cyclin E-cdk 2 activation and retinoblastoma protein phosphorylation.

In glomerular disease, transforming growth factor-beta1 (TGF-beta1) has been demonstrated to exert anti-mitogenic and anti-inflammatory as well as fibrogenic effects. To better understand the TGF-beta1 action on glomerular cells at the molecular level, we investigated mechanisms of TGF-beta1-induced growth suppression in primary cultures of rat mesangial cells (MCs). TGF-beta1 (5 ng/ml) markedly inhibited proliferation of MCs incubated with PDGF, endothelin-1, bFGF, serotonin, or EGF, indicating that TGF-beta1 interferes with post-receptor signals of mitogenesis. TGF-beta1 did not affect mitogen-stimulated induction of the immediate early genes, c-fos, c-jun, and Egr-1 in MCs that occurred transiently at 30 to 120 minutes. Time-course studies revealed that TGF-beta1 inhibited DNA synthesis and MC replication when added up to six to eight hours after MC stimulation with PDGF. FACS analysis demonstrated that MCs had reached middle to late G1 phase of cell cycle progression at this timepoint. PDGF stimulation of MCs induced protein expression of the G1 phase cyclin D1 as well as the cyclin-dependent kinases cdk 4 and cdk 2. This was not significantly altered when MCs were coincubated with both, PDGF and TGF-beta1. However, TGF-beta1 prevented PDGF-elicited phosphorylation of the retinoblastoma tumor suppressor (pRb), a negative cell cycle regulator. Moreover, TGF-beta1 significantly reduced cyclin E-associated histone H1 kinase activity in the presence of PDGF. These results indicate that TGF-beta1 inhibits mitogen-stimulated MC growth by causing cell cycle arrest in late G1 phase. While TGF-beta1 does not alter the mitogen-induced expression and abundance of G1 phase cyclin D1 and cdks 4 and 2 in MCs, it inhibits cyclin E-cdk 2 activity, thus preventing mitogen-elicited phosphorylation and inactivation of pRb in G1 phase and transition to S phase.

Animals↗
PubMed1997

Adhesion molecules in the glomerular mesangium.

Experimental evidence indicates that extensive "cross-talk" exists between glomerular cells, extracellular matrix molecules and soluble mediator substances affecting the proliferative and secretory phenotype of glomerular mesangial cells. Both matrix and cytokines regulate mesangial cell behavior in vitro and in vivo after binding to specific cell surface receptors. It appears as if the concerted action of insoluble and soluble ligands on mesangial cells involves a reciprocal regulation of matrix molecules and cytokines as well as expression and affinity of their respective receptors. Elucidation of the potential biologic and clinical relevance of cell-matrix interactions in the glomerular mesangium represents a challenging goal in current kidney research. This brief review summarizes recent investigations concerning regulation of expression and function of adhesion molecules and matrix receptors in the mesangium. In addition to results from cell culture studies, descriptive findings on expression and regulation of adhesion molecules and their potential role for altered mesangial cell behavior in glomerular disease is considered.

Animals↗
PubMed1997

Differential regulation of chemokines by leukemia inhibitory factor, interleukin-6 and oncostatin M.

M. Leukemia inhibitory factor (LIF). oncostatin M (OsM) and interleukin-6 (IL-6) are members of a cytokine family, which are produced by activated macrophages and glomerular mesangial cells. These cytokines have been implicated in the pathogenesis of glomerular inflammation, but their action on glomerular cells is presently unclear. Therefore, we examined the effects of IL-6, OsM and LIF on chemokine synthesis of rat mesangial cells in culture. While LIF as well as IL-6 up-regulated monocyte chemotactic protein-1 (MCP-1) mRNA expression, OsM showed no such effect. The induction of MCP-1 mRNA by LIF and IL-6 was transient, peaking at one to two hours and two to three hours, respectively, and returning to background levels within several hours. Induction of MCP-1 mRNA by LIF and IL-6 was strongly inhibited by dexamethasone. LIF activated STAT factors in mesangial cells, suggesting their involvement in signal transduction pathways that lead to LIF-stimulated up-regulation of MCP-1 mRNA. By contrast, LIF. IL-6 and OsM failed to affect the expression of the chemokines, macrophage inflammatory protein-2 (MIP-2) and RANTES. The rapid, transient and differential regulation of MCP-1 expression induced by LIF and IL-6 contrasted with uniformly powerful effects of the proinflammatory cytokines IL-1 beta and TNF alpha that induced all tested chemokines for prolonged time periods. These results suggest that the selective and transient induction of MCP-1 by LIF and IL-6 may play a role in the preferential attraction of monocytes to the injured glomerulus.

Animals↗
PubMed1997

Glomerular epithelial cell products stimulate mesangial cell proliferation in culture.

Glomerular epithelial cells (GEC) and mesangial cells (MC) are both involved in glomerular diseases. To elucidate potential interactions between these glomerular cell types, we examined whether products of GEC affect the proliferative activity of MC. We found that cultured rat GEC secrete soluble factors into the supernate (GEC-CM) that induce proliferation of quiescent rat MC. The mitogenic activity was trypsin sensitive and partially heat-labile. Biochemical analysis of GEC-CM by gel filtration HPLC, reverse phase HPLC, and isoelectric focusing revealed at least three mitogenic fractions as well as inhibitory activity present in GEC-CM. Competitive binding assays with 125I-labeled PDGF did not show significant amounts of PDGF in GEC-CM. The biochemical features of the GEC-derived MC growth factors are distinct from IL-6, PDGF, bFGF, and endothelin, previously described GEC-derived MC growth factors. Additionally, significant contributions of known growth factors such as IL-1, IL-2, IL-3, IL-4, IL-5, TNF alpha, TGF beta, and GM-CSF are unlikely. The results indicate that GEC produce several biochemically-distinct MC growth regulators. While these epithelial cell-derived mitogens for MC require further characterization, they may play an important role in the regulation of MC replication, such as during embryogenesis and glomerular disease.

Animals↗
PubMed1997

Expression of cell adhesion molecules in primary renal disease and renal allograft rejection.

BACKGROUND: In vitro studies have demonstrated that inflammatory mediators such as the cytokines TNF alpha and IL-1 upregulate or induce de novo expression of cell adhesion molecules on endothelial and epithelial cells. In the present study the expression of the cell adhesion molecules ICAM-1, VCAM-1, E-selectin and PECAM-1 was investigated in renal biopsies from patients with primary renal diseases (n = 66) and from renal allograft recipients (n = 42). METHODS: Expression of the cell adhesion molecules was determined by immunohistochemistry of frozen sections using monoclonal antibodies directed against PECAM-1, ICAM-1, VCAM-1, E-selectin and MHC class II molecules (APAAP method). RESULTS AND CONCLUSIONS: PECAM-1 and ICAM-1 were expressed in the renal vasculature and disappeared in obliterated glomeruli with endothelial cell destruction. ICAM-1 but not PECAM-1 was upregulated in renal endothelia in acute allograft rejection and inflammatory primary renal diseases. Tubular de novo expression of ICAM-1 and VCAM-1 correlated with severe structural damage of the renal parenchyma including interstitial fibrosis. Vascular and/or glomerular VCAM-1 and E-selectin expression was pronounced in severe acute allograft rejection and also reflected the intensity of inflammatory reactions in primary renal diseases with or without autoimmune disorders. De novo expression of VCAM-1 and E-selectin in renal vessels and/or glomeruli and overexpression of ICAM-1 are markers of acute and severe inflammatory processes in biopsies from allograft recipients and patients with primary renal diseases.

E-Selectin↗
PubMed1997

Factors controlling growth and matrix production in vascular smooth muscle and glomerular mesangial cells.

The vasculature wall is an active, integrated organ composed of endothelial cells and vascular smooth muscle cells, as well as other cell types depending on the specific vascular segment (e.g. fibroblasts in many vascular regions). The vascular wall is not static; the vascular components (cells and extracellular matrix) dynamically increase, decrease or reorganize, or both, in response to physiological and pathological stimuli. The vascular smooth muscle cells are the final common pathway for many of these dynamic changes in vascular wall structure. In the renal glomerulus, however, the glomerular mesangial cells-a cell phenotypically related to the vascular smooth muscle cells-also participate. Although sometimes beneficial, changes in vascular or glomerular structure often lead to cardiovascular (e.g. atherosclerosis, restenosis, intimal hyperplasia) and renovascular (e.g. glomerulosclerosis) diseases. Consequently, much effort has been expended to elucidate the mechanisms that control growth and extracellular matrix production by vascular smooth muscle cells and glomerular mesangial cells. The purpose of this review is to discuss recent developments.

Angiotensin II↗
PubMed1996

Transcription factor Egr-1 regulates glomerular mesangial cell proliferation.

Increase of glomerular mesangial cells (MCs) is a prominent histopathological finding in many types of glomerulonephritis. We have shown previously that expression of the zinc-finger transcription factor, early growth response gene-1 (egr-1), is closely correlated with the proliferation of cultured MCs. To elucidate whether Egr-1 is required for MC proliferation, we inhibited serum-induced Egr-1 expression by phosphothioate-modified antisense oligonucleotides (ODNs). Uptake of antisense ODNs into MCs was demonstrated, and five different egr-1 antisense ODNs were tested for their impact on serum-induced egr-1 mRNA and protein levels and on MC growth. The most potent egr-1 antisense ODN inhibited serum-induced egr-1 mRNA by 68%, protein induction by 58%, and MC replication as measured by [3H]thymidine uptake and cell counts by 78 and 46%, respectively. The effects of antisense ODNs on MC growth correlated closely with their ability to inhibit Egr-1 protein. ODNs acted in a dose-dependent manner, the minimal effective concentration being 1 microM. Control ODNs had no significant effects. In addition, antisense ODNs against egr-1 potently inhibited endothelin-1-induced Egr-1 expression and MC growth. Heparin, a known inhibitor of MC growth, suppressed serum-induced [3H]thymidine uptake by 39% and egr-1 mRNA expression by 44%. We conclude that Egr-1 is an essential part of the mitogenic signal transduction cascade in cultured MCs.

Animals↗
PubMed1996

Cloning and sequencing of the proximal promoter of the rat iNOS gene: activation of NFkappaB is not sufficient for transcription of the iNOS gene in rat mesangial cells.

It has previously been shown that expression of the inducible form of NO synthase (EC 1.14.23) is controlled at the transcriptional level and that induction of iNOS transcription is dependent on activation of transcription factors of the NFkappaB family. TNF-alpha and IL-1beta synergistically stimulate iNOS transcription in rat glomerular mesangial cells. We have recently reported that endothelin-1 completely blocks cytokine-induced iNOS expression at the transcriptional level. To further investigate the molecular mechanisms and the role of NFkappaB in cytokine-elicited iNOS transcription, we cloned a 661 bp genomic rat DNA fragment, which contains 497 bp of the proximal iNOS promoter. An NFkappaB-binding site identical to that described for the murine sequence was identified and used for electrophoretic mobility shift experiments. We found that binding of NFkappaB is strongly induced in mesangial cells by both IL-1beta and TNF-alpha. While endothelin-1 blocks cytokine-induced iNOS expression, it has no influence on the binding pattern of NFkappaB. We conclude from these data that transcription of iNOS in mesangial cells requires additional signals besides activation of NFkappaB.

Animals↗
PubMed1996

Cell-matrix interactions in the glomerular mesangium.

Specific interactions between cells and components of the surrounding extracellular matrix (ECM) or underlying basement membrane have been shown to modulate cell behavior, including cellular responses to soluble regulator molecules. In addition to the long-recognized role of such interactions in cell localization, anchoring and differentiation during embryogenesis, they are also involved in diverse processes such as maintenance of tissue integrity, response of cells to mechanical stress, inflammatory response, wound healing, tumor cell growth and metastasis as well as apoptosis. Over the last several years, evidence has been reported that extensive "cross-talk" between glomerular mesangial cells (MCs), ECM molecules and soluble mediator substances also affects the proliferative and synthetic phenotype of MCs. This is likely to be relevant for the behavior of MCs during embryonic development, tissue repair and disease processes of glomeruli. The potential biologic and clinical relevance of cell-matrix interactions in the glomerulus makes their elucidation a challenging goal in current kidney research. In this brief review, we present selected aspects of recent investigations concerning the mesangial matrix and its interactions with MCs. In addition to results from cell culture studies, descriptive findings on abnormalities of the ECM and their potential role for the altered MC behavior in glomerular disease will also be discussed.

Animals↗
PubMed1996

Adenine dinucleotides: a novel class of signalling molecules.

1. Adenine dinucleotides (Ap3A, Ap4A, Ap5A, Ap6A) are stored in secretory granules of thrombocytes, chromaffin cells and neuronal cells. After release into the extracellular space, the dinucleotides exhibit divergent biological effects on a variety of target cells and organs. The dinucleotides are metabolized by soluble enzymes in the blood plasma as well as by membrane-bound ectoenzymes of endothelial cells, smooth muscle cells, and other cell types. 2. The enzymatic cleavage of the dinucleotides plays a dual role for their biological function: (a) termination of the signal; and (b) generation of purinergically active products such as ATP, ADP and finally adenosine. In contrast to ATP the dinucleotides are long-lived purine nucleotides in the blood. 3. The potential role of the dinucleotides as signalling molecules has been demonstrated in several systems. The adenosine polyphosphates have autocrine function for thrombocytes. Ap3A at low concentration reversibly activates isolated platelets. The mechanism of activation has been elucidated by showing a continuous cleavage of Ap3A, leading to the formation of ADP which is a known agonist of the P2T receptor on thrombocytes. Ap4A and other dinucleotides act as antagonists and inhibit platelet activation. 4. The vasotone of perfused isolated arteries as well as of resistance vessels in the beating heart is differentially influenced by adenine dinucleotides. While Ap3A and Ap4A exhibit relaxing effects at micromolar concentrations, Ap5A and Ap6A elicit vasoconstriction in these vessels. 5. In rat kidney mesangial cells adenine dinucleotides efficiently promote growth. Stimulation of DNA synthesis by various growth factors is enhanced synergistically. ApnA significantly increase the expression of the early growth response gene Egr-1. 6. The specificity and, in some tissues, the uniqueness of effects evoked by dinucleotides may be mediated by genuine dinucleotide receptors (P4) or by specialized P2 receptors (P2D).

Animals↗
PubMed1996

Extracellular nucleotides as signalling molecules for renal mesangial cells.

1. Glomerular diseases frequently cause chronic renal failure which ultimately requires dialysis and kidney transplantation. The events leading to destruction of the glomerular filtration apparatus include injury of glomerular cells, aggregation of thrombocytes and infiltration of immune cells into the glomerulus. 2. Nucleotides (e.g. ATP and UTP) are present in all glomerular cell types as well as in thrombocytes. The release of nucleotides into the extracellular space occurs after damage of glomerular cells and aggregation of thrombocytes. Several in vitro and in vivo findings indicate that extracellular nucleotides may play a role as pro-inflammatory mediators in glomerulonephritis. 3. A hallmark finding in kidney biopsies from patients with glomerulonephritis is proliferation of glomerular mesangial cells. Cell culture studies demonstrated that extracellular ATP (10-300 microM) stimulated growth of mesangial cells. The mitogenic effect of ATP was potentiated in the presence of multiple growth factors. 4. Nucleotide-induced signalling in mesangial cells included an increase of intracellular calcium, activation of phosphatidylinositol-specific phospholipase C and phospholipase D, inhibition of adenylylcyclase, stimulation of mitogen-activated protein kinase and increased expression of the immediate early genes, c-fos, c-jun and Egr-1. 5. In previous studies of experimental mesangioproliferative glomerulonephritis, exogenously given ADP beta S and ATP gamma S have been shown to aggravate the course of the disease, while 2-chloroadenosine had beneficial effects. 6. Taken together, these findings support the concept that nucleotides may function as proinflammatory mediators in glomerulonephritis while adenosine may have antiinflammatory effects.

Adenosine Triphosphate↗