Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: EC:2.4.2.30 (
PARP
)
13,611
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Suppression of apoptosis by glucocorticoids in glomerular endothelial cells: effects on proapoptotic pathways. 1078 Sep 73
Necrotic lesions and necrotic cell death characterize severe autoimmune nephritides, and contribute to local inflammation and to progression of the disease. Poly(ADP-ribose) polymerase-1 (
PARP-1
), a DNA repair enzyme, is involved in the induction of necrosis and is a key player in the acute and chronic inflammation. Therefore, we hypothesized that
PARP-1
controls the severity of nephritis by mediating the induction of necrosis in the kidney. We used lupus and anti-glomerular basement membrane models of nephritis to determine the effects of
PARP-1
on the inflammatory response in the kidney. We show in this study that
PARP-1
is indeed activated during the course of
glomerulonephritis
. We also show that the absence of
PARP-1
or its pharmacological inhibition results in milder nephritis, with lower blood urea nitrogen levels, reduced necrotic lesions, and higher survival rates. The relevance of
PARP-1
showed a strong male sex specificity, and treatment of male mice with 17beta-estradiol prolonged their survival during the course of nephritis.
PARP-1
also regulated TNF-alpha expression and up-regulation of adhesion molecules, further supporting a role of
PARP-1
in the inflammatory process within the kidney. Our results demonstrate that
PARP-1
activation and consequent necrotic cell death play an important role in the pathogenesis of male nephritis, and suggest that
PARP-1
can be a novel therapeutic target in
glomerulonephritis
.
...
PMID:Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. 1945 27
