Chronic Treatment with Angiotensin II Type 1 Receptor Antagonist Suppresses Glomerular Activator Protein–1 Activity in Salt–Sensitive Hypertensive Rats

Abstract

We examined the effects of angiotensin–converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor antagonist (AT1a) on the action of protooncogene c–fos in salt–sensitive hypertensive rats. Seven–week old Dahl salt–sensitive rats fed a high (8%)–salt diet were treated with ACEI, cilazapril (10 mg/kg) or AT1a, TCV–116 (1mg/ kg) every day for 6 weeks. The control animals were fed a low (0.3%)–salt diet. Systolic blood pressure gradually increased in high–salt–loaded rats and was higher than low–salt–treated rats throughout the study. However, both medications had no significant antihypertensive effect. After 6 weeks of therapy, glomerular mRNA and nuclear protein were extracted from the resected kidneys. Competitive reverse transcription–polymerase chain reaction showed a high level of glomerular c–fos mRNA in high–salt–loaded rats and that ACEI or AT1a treatment did not significantly change its level. Electrophoretic mobility shift assay demonstrated that treatment with AT1a significantly decreased the activator protein–1 (AP–1) binding activity in the glomerular nuclear extract compared to ACEI. Our findings suggest that, compared with ACEI treatment, long–term treatment with AT1a may contribute to attenuation of the glomerular injury in salt–sensitive hypertension by inhibiting AP–1 transcription activity independent of its antihypertensive effect.

AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan

“…The results with ACE inhibition were not surprising, however, as non-ACE-mediated renal production of angiotensin II was likely sustained despite ACE inhibition (18,38). Consistent with this hypothesis, previous data by Otsuka et al (41,42) and Noda et al (39,40) suggested greater renoprotective effects when direct AT 1A inhibition was utilized compared with ACE inhibition in various models of renal injury.…”

Effects of L/N-Type Calcium Channel Antagonist, Cilnidipine on Progressive Renal Injuries in Dahl Salt-Sensitive Rats

“…Although this discrepancy has been also demonstrated with other calcium channel antagonists, the exact mechanism is still unknown. 15,16) In this study, antihypertensive effects of cilnidipine were sustained during the treatment period, but the blood pressure level may have not sufficient to reduce the urinary protein excretion in a se-vere renal disease model. High dose treatment studies are needed to confirm the effect of cilnidipine on proteinuria in Dahl rats.…”

“…[14][15][16] It has been suggested that sympathetic nerve activity is increased or easy to increase by physical stress in Dahl S rats on a high-salt diet.…”

“…[14][15][16] It has been suggested that sympathetic nerve activity is increased or easy to increase by physical stress in Dahl S rats on a high-salt diet. 17,18) Wu et al 19) reported that high-salt induced changes in intrarenal vessel structure and renal haemodynamic function in Dahl S rats are dependent on the activity of the sympathetic nervous system.…”

Role of Bradykinin in Renoprotective Effects by Angiotensin II Type 1 Receptor Antagonist in Salt-Sensitive Hypertension.

“…We have previously shown that the administration of AT1A ameliorates the glomerular damage caused by chronic salt-sensitive hypertension without lowering systemic blood pressure. This effect was attributed to AT1A-induced suppression of the expression of transforming growth factor-β1 in glomeruli (13), which in turn was induced by inhibition of activator protein-1 activity (14). Given that AT1A are capable of enhancing the AT2-bradykinin system in vivo (15,16), the underlying mechanism whereby AT1A prevents glomerular damage in saltsensitive hypertension most likely involves the activation of endogenous AT2 receptor signaling, which, in turn, counteracts the effects of AT1 activation.…”