Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways

Abstract

1 Tumour necrosis factor-a (TNF-a)-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. 2 Co-treatment of cells with 10 nM dexamethasone and TNF-a 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. 3 To mechanistically elucidate the action of glucocorticoids we evaluated whether glucocorticoids elicit a time-dependent eect. For dexamethasone, to maximally inhibit DNA fragmentation a preincubation period was not required. Even if dexamethasone was supplemented 6 h following TNF-a or LPS we observed a maximal inhibitory eect. 4 Concerning its in¯uence on TNF-a and LPS signal transduction, we found that dexamethasone only partially prevented cytochrome-c-release as a ®rst sign of apoptotic cell death but eciently blocked mitochondrial permeability transition. Moreover, TNF-a-and LPS-induced Bak upregulation, Bcl-X L -downregulation, and the activation of caspase-3-like proteases, measured uorometrically using DEVD-AMC and PARP cleavage, were eciently blocked by dexamethasone. 5 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.

Glucocorticoids Inhibit Apoptosis during Fibrosarcoma Development by Transcriptionally Activating Bcl-xL

“…The reported increased expression of Bcl-x L mRNA in human myeloid leukemic cells required 24 h of hormone treatment (48), whereas we clearly detected up-regulation of Bcl-x L after 2 h of dexamethasone treatment. Subsequent studies by other groups have also demonstrated the importance of increasing Bcl-x L expression for the inhibition of apoptosis by glucocorticoids in a variety of cell types (3,8,31,49). However, none of these reports identified the mechanism by which GR might control Bcl-x expression.…”

Glucocorticoid receptor and breast cancer

“…In breast and other origin cancer cells, the synthetic glucocorticoid, dexamethasone (DEX), induces the expression of genes frequently associated with protection against cell apoptosis, such as Bcl-xL, Bak, SGK-1 and MKP-1 [16,17,23,24,57]. Concomitantly, DEX also reinforces its survival effect by the downregulation of pro-apoptotic genes, such as Bid, TRAIL and GR-dependent gene tissue plasminogen activator (tPa) [24].…”

“…GCs have been shown to specifically inhibit chemotherapeutic anti-tumor activities in human breast preclinical model by decreasing cellular apoptosis resulting in larger tumor volumes [15-18, 23, 24]. mRNA expression analysis in xenograft tumors, excised from mice exposed to systemic GCs treatment, demonstrated an upregulation of anti-apoptotic genes, such as Bcl-xL, Bak, SGK-1, or MKP-1 [16,17,23,25,57]. Interestingly, MKP-1 overexpression has also been observed in primary human breast and prostate tumors context [87,88].…”

Loss of TIMP3 Enhances Interstitial Nephritis and Fibrosis

“…49 TNF␣-induced injury is mediated via both its receptors, TNFR1 and TNFR2, with clear evidence for a proapoptotic role in renal tissue. 33,49,50 In this study we identify TIMP3 as a critical negative regulator of renal TNF␣ activity. In the absence of the negative regulatory function of TIMP3, TNF␣ further triggers apoptosis and inflammation, as also reported in a wide range of pathophysiological conditions.…”