Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure.

Abstract

The intrarenal renin-angiotension system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in the circulating counterpart in this model of experimental heart failure, and

Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells.

“…The tyrosine kinase inhibitor genistein significantly decreased both All-and PMA-stimulated PAI-2 expression in both RASMC and RME cells. Tyrosine kinase inhibitors have been shown to block the endothelin-l-stimulated induction of cfos and activation of AP-1 cis-element activity in glomerular mesangial cells (51). Since Cousins et al (35) have shown that two AP-1 binding sites in the 5' flanking region of the PAI-2 promoter are required for the PKC-stimulated transcription of PAI-2, this effect of tyrosine kinase inhibition by genistein may also apply to the PKC-dependent mechanism of All-stimulated PAI-2 expression.…”

Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan

“…kidney vessels; angiotensin-converting enzyme; laser microcapture THE RENIN-ANGIOTENSIN SYSTEM (RAS) plays a key role in the control of cardiovascular and renal function (8,13,30). Activation of the RAS has been widely incriminated in the pathophysiology of renal and cardiovascular diseases such as hypertension, myocardial infarction, and heart failure (21,25). The RAS system primarily involves two enzymes: renin, which cleaves angiotensinogen to the inactive decapeptide angiotensin (ANG) I, and angiotensin-converting enzyme (ACE), a dipeptidyl carboxypeptidase that hydrolyzes ANG I to the octapeptide ANG II (7,26).…”

Influence of myocardial infarction on changes in the expression of angiotensin type 1 receptor in the rat prostate

“…These changes comprise both protein and mRNA level. Numerous studies have shown that MI has a significant impact on changes in the RAS system components, such as expression of angiotensin receptors, or angiotensin-converting enzyme activity in various tissues [7,[34][35][36]. In vivo and in vitro experiments have shown that MI provokes a dramatic up-regulation of both angiotensin receptor subtypes in different organs [34,37,38].…”