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 o n glomerular mitogen-activated protein kinases (MAPK), including extra cellular 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. D NA binding activity of AP-1 and Sp 1 was determined by gel mobility sh ift assay. Continuous infusion of Ang II (1000 ng/kg per min, intraven ously) to conscious rats rapidly increased BP, followed by the rapid a nd 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 w as increased 2.6-fold (P < 0.01) at 24 h after the start of Ang II inf usion. Supershift analysis showed that the activated AP-1 complexes co ntained c-Fos and c-Jun proteins. On the other hand, glomerular Sp 1 D NA 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 hypert ension-induced glomerular injury.