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1.
Exp Mol Pathol ; 70(3): 265-73, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11418005

ABSTRACT

The vasoactive peptide angiotensin II is the principal effector of the renin-angiotensin system. It exerts mitogenic and growth-inhibiting effects in many target tissues, including renal mesangial cells. To investigate mechanisms of angiotensin II signaling in human mesangial cells, we explored the signal transducer and activator of transcription (STAT) pathway as a possible regulator of angiotensin II receptor-specific signaling. We tested whether angiotensin II could induce STAT activation and nuclear translocation of STAT proteins in human mesangial cells by electromobility shift assays and by immunostaining and confocal microscopy. We found that fetal human mesangial cells express STAT1,2,3,5, and 6 and that stimulation of these cells by angiotensin II results in rapid induction of STAT1 and STAT5 DNA-binding activity. This DNA-binding activity was identified as STAT5 for angiotensin receptor type 1 activation and STAT1 for angiotensin receptor type 2-mediated activation, as induction of STAT-DNA binding by angiotensin II could be differentially blocked by the angiotensin receptor type 1 blocker losartan and by angiotensin II receptor type 2 blocker PD 123,319. Angiotensin II also induced STAT1 and STAT5 tyrosine phosphorylation and nuclear translocation of activated STATs in a receptor subtype-specific manner. STAT activation thus appears to provide an important signaling pathway for angiotensin II-induced cellular responses.


Subject(s)
Angiotensin II/pharmacology , DNA-Binding Proteins/metabolism , Glomerular Mesangium/physiology , Milk Proteins , Receptors, Angiotensin/physiology , Trans-Activators/metabolism , Cells, Cultured , Fetus , Glomerular Mesangium/cytology , Glomerular Mesangium/drug effects , Humans , Kinetics , Phosphorylation , Protein Transport , Receptor, Angiotensin, Type 1 , Receptor, Angiotensin, Type 2 , STAT1 Transcription Factor , STAT2 Transcription Factor , STAT5 Transcription Factor
2.
Am J Physiol ; 277(2): F227-34, 1999 08.
Article in English | MEDLINE | ID: mdl-10444577

ABSTRACT

Renal ischemia causes a rapid fall in cellular ATP, increased intracellular calcium (Ca(i)), and dissociation of Na(+)-K(+)-ATPase from the cytoskeleton along with initiation of a stress response. We examined changes in Ca(i), Na(+)-K(+)-ATPase detergent solubility, and activation of heat-shock transcription factor (HSF) in relation to graded reduction of ATP in LLC-PK(1) cells to determine whether initiation of the stress response was related to any one of these perturbations alone. Ca(i) increased first at 75% of control ATP. Triton X-100 solubility of Na(+)-K(+)-ATPase increased below 70% control ATP. Reducing cellular ATP below 50% control consistently activated HSF. Stepped decrements in cellular ATP below the respective thresholds caused incremental increases in Ca(i), Na(+)-K(+)-ATPase solubility, and HSF activation. ATP depletion activated both HSF1 and HSF2. Proteasome inhibition caused activation of HSF1 and HSF2 in a pattern similar to ATP depletion. Lactate dehydrogenase release remained at control levels irrespective of the degree of ATP depletion. Progressive accumulation of nonnative proteins may be the critical signal for the adaptive induction of the stress response in renal epithelia.


Subject(s)
Kidney/physiopathology , Stress, Physiological/physiopathology , Adenosine Triphosphate/deficiency , Animals , Calcium/metabolism , Cysteine Endopeptidases/drug effects , Cysteine Endopeptidases/metabolism , DNA-Binding Proteins/metabolism , Detergents , Differential Threshold , Epithelial Cells/metabolism , Epithelial Cells/physiology , Heat Shock Transcription Factors , Heat-Shock Proteins/metabolism , Intracellular Membranes/metabolism , Kidney/metabolism , Kidney/pathology , L-Lactate Dehydrogenase/metabolism , LLC-PK1 Cells , Multienzyme Complexes/drug effects , Multienzyme Complexes/metabolism , Octoxynol , Proteasome Endopeptidase Complex , Sodium-Potassium-Exchanging ATPase/analysis , Sodium-Potassium-Exchanging ATPase/chemistry , Solubility , Stress, Physiological/metabolism , Swine , Transcription Factors/metabolism
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