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Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways.
Br J Pharmacol 2000; 129(8):1673-83BJ

Abstract

Tumour necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced apoptosis of bovine glomerular endothelial cells is now recognized as an important part in the pathogenesis of glomerulonephritis characterized by early mitochondrial cytochrome c release, mitochondrial permeability transition, Bak protein upregulation, Bcl-X(L) protein downregulation and caspase-3 activation. Co-treatment of cells with 10 nM dexamethasone and TNF-alpha or LPS blocked roughly 90% of apoptotic cell death in glomerular endothelial cells. The action of glucocorticoids could be documented in that they prevented all apoptotic markers such as DNA laddering, DNA fragmentation measured by the diphenylamine assay as well as morphological alterations. To mechanistically elucidate the action of glucocorticoids we evaluated whether glucocorticoids elicit a time-dependent effect. For dexamethasone, to maximally inhibit DNA fragmentation a preincubation period was not required. Even if dexamethasone was supplemented 6 h following TNF-alpha or LPS we observed a maximal inhibitory effect. Concerning its influence on TNF-alpha and LPS signal transduction, we found that dexamethasone only partially prevented cytochrome-c-release as a first sign of apoptotic cell death but efficiently blocked mitochondrial permeability transition. Moreover, TNF-alpha- and LPS-induced Bak upregulation, Bcl-X(L)-downregulation, and the activation of caspase-3-like proteases, measured fluorometrically using DEVD-AMC and PARP cleavage, were efficiently blocked by dexamethasone. We postulate that glucocorticoids exert their inhibitory action upstream of the terminal death pathways but downstream of primary receptor mediated signals by blocking pro-apoptotic signals pre- and/or post cytochrome c release and mitochondrial signalling.

Authors+Show Affiliations

Zentrum der Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. U.Messmer@em.uni-frankfurt.deNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10780973

Citation

Messmer, U K., et al. "Suppression of Apoptosis By Glucocorticoids in Glomerular Endothelial Cells: Effects On Proapoptotic Pathways." British Journal of Pharmacology, vol. 129, no. 8, 2000, pp. 1673-83.
Messmer UK, Winkel G, Briner VA, et al. Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways. Br J Pharmacol. 2000;129(8):1673-83.
Messmer, U. K., Winkel, G., Briner, V. A., & Pfeilschifter, J. (2000). Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways. British Journal of Pharmacology, 129(8), pp. 1673-83.
Messmer UK, et al. Suppression of Apoptosis By Glucocorticoids in Glomerular Endothelial Cells: Effects On Proapoptotic Pathways. Br J Pharmacol. 2000;129(8):1673-83. PubMed PMID: 10780973.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways. AU - Messmer,U K, AU - Winkel,G, AU - Briner,V A, AU - Pfeilschifter,J, PY - 2000/4/26/pubmed PY - 2000/7/8/medline PY - 2000/4/26/entrez SP - 1673 EP - 83 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 129 IS - 8 N2 - Tumour necrosis factor-alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced apoptosis of bovine glomerular endothelial cells is now recognized as an important part in the pathogenesis of glomerulonephritis characterized by early mitochondrial cytochrome c release, mitochondrial permeability transition, Bak protein upregulation, Bcl-X(L) protein downregulation and caspase-3 activation. Co-treatment of cells with 10 nM dexamethasone and TNF-alpha or LPS blocked roughly 90% of apoptotic cell death in glomerular endothelial cells. The action of glucocorticoids could be documented in that they prevented all apoptotic markers such as DNA laddering, DNA fragmentation measured by the diphenylamine assay as well as morphological alterations. To mechanistically elucidate the action of glucocorticoids we evaluated whether glucocorticoids elicit a time-dependent effect. For dexamethasone, to maximally inhibit DNA fragmentation a preincubation period was not required. Even if dexamethasone was supplemented 6 h following TNF-alpha or LPS we observed a maximal inhibitory effect. Concerning its influence on TNF-alpha and LPS signal transduction, we found that dexamethasone only partially prevented cytochrome-c-release as a first sign of apoptotic cell death but efficiently blocked mitochondrial permeability transition. Moreover, TNF-alpha- and LPS-induced Bak upregulation, Bcl-X(L)-downregulation, and the activation of caspase-3-like proteases, measured fluorometrically using DEVD-AMC and PARP cleavage, were efficiently blocked by dexamethasone. We postulate that glucocorticoids exert their inhibitory action upstream of the terminal death pathways but downstream of primary receptor mediated signals by blocking pro-apoptotic signals pre- and/or post cytochrome c release and mitochondrial signalling. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/10780973/Suppression_of_apoptosis_by_glucocorticoids_in_glomerular_endothelial_cells:_effects_on_proapoptotic_pathways_ L2 - https://doi.org/10.1038/sj.bjp.0703255 DB - PRIME DP - Unbound Medicine ER -