Activation of glomerular mitogen-activated protein kinases in angiotensin II-mediated hypertension.
The in vivo signal transduction pathway, responsible for hypertension-induced glomerular injury, remains to be clarified. In this study, the effect of angiotensin II (Ang II)-induced hypertension was examined on glomerular mitogen activated protein kinases (MAPK), including extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), and on glomerular transcription factors activator protein-1 (AP-1) and Sp 1. MAPK activities were determined by in-gel kinase assay. DNA binding activity of AP-1 and Sp 1 was determined by gel mobility shift assay. Continuous infusion of Ang II (1000 ng/kg per min, intravenously) to conscious rats rapidly increased BP, followed by the rapid and transient activation of glomerular p42 and p44 ERK and p46 and p55 JNK with the peak at 15 to 180 min. Glomerular AP-1 binding activity was increased 2.6-fold (P < 0.01) at 24 h after the start of Ang II infusion. Supershift analysis showed that the activated AP-1 complexes contained c-Fos and c-Jun proteins. On the other hand, glomerular Sp 1 DNA binding activity was not changed throughout 7 d of Ang II infusion. These results provided the first in vivo evidence that Ang II-induced hypertension causes the activation of glomerular ERK and JNK, leading to the activation of AP-1. Thus, ERK and JNK signaling cascades, via the activation of AP-1, may be implicated in the development of hypertension-induced glomerular injury.
Hamaguchi
A
A
Department of Pharmacology, Osaka City University Medical School, Japan.
Kim
S
S
Yano
M
M
Yamanaka
S
S
Iwao
H
H
D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects; D004789:Enzyme Activation; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology*; D007262:Infusions, Intravenous; D048031:JNK Mitogen-Activated Protein Kinases; D007678:Kidney Glomerulus / Q000201:enzymology; D008297:Male; D020928:Mitogen-Activated Protein Kinases; D051381:Rats; D017207:Rats, Sprague-Dawley; D016329:Sp1 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000494:pharmacology
D004268:DNA-Binding Proteins; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases